Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 09/21/01. The protocol was agreed in October 2009. The assessment report began editorial review in March 2010 and was accepted for publication in October 2010. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

none

Copyright statement

© Queen’s Printer and Controller of HMSO 2011. This work was produced by Hislop et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2011 Queen’s Printer and Controller of HMSO

Description of health problem

Current service provision

Description of technology under assessment

Decision problem

Specific information on the population, interventions, comparators and relevant outcomes considered for this review are discussed in detail in Chapter 4 (see Identification of studies).

Until the licensing of imatinib, the prognosis for people with unresectable and/or metastatic GISTs was poor. 19 Since 2002, the clinical effectiveness of treatment for GIST with imatinib at a dose of 400 mg/day has been well documented. 50,55 There is also clinical trial evidence showing that patients with unresectable and/or metastatic GIST can also respond to higher doses of imatinib, up to a maximum tolerated dose of 800 mg/day,40 and that patients with different exon mutations in the KIT gene may differ in their response to imatinib at both standard and escalated doses. 14

Guidance from NICE does not currently recommend the prescription of escalated doses of imatinib upon progression on the standard 400 mg/day dose,50 although it is common in clinical practice. 15,32 Most of the evidence relating to dose-escalated imatinib comes from randomised trials where participants were randomised to doses greater that 400 mg/day, as opposed to receiving these higher doses upon disease progression on the 400 mg/day dose. However, evidence suggests that tolerability of higher doses may depend on the extent of prior exposure to the drug,66 and if in clinical practice escalated doses are prescribed only upon progression, these trial data may not provide reliable estimates of response, progression-free survival (PFS) and overall survival (OS), quality-of-life effects or the extent of adverse event occurrence. In addition, if patients with unresectable and/or metastatic GIST are likely to attain different levels of clinical benefit from different imatinib doses then clinicians’ decision-making on appropriate dosages for individual patients should be informed by the best available evidence.

The development of imatinib has represented a paradigm shift in the treatment of unresectable and/or metastatic GIST, as, prior to its introduction onto the market, the only available treatment remaining for this population group was BSC, which, given the severity of this disease, represents essentially palliative intervention. Since the introduction of imatinib, other new treatments for unresectable and/or metastatic GIST have become available, including sunitinib, which has been recommended by NICE as the second-line treatment for the population of interest, after failure on treatment with imatinib. 51 As there are now various options available for treating unresectable and/or metastatic GIST, it is therefore necessary to review the available evidence on imatinib at escalated doses, when compared with sunitinib, for patients with unresectable and/or metastatic GIST, whose disease has progressed on the standard imatinib dose of 400 mg/day.

Overall aims and objectives

The aim of this review was to assess the clinical effectiveness and cost-effectiveness of imatinib at escalated doses (i.e. 600 or 800 mg/day) within its licensed indication,67 for the treatment of patients with unresectable and/or metastatic GISTs, who have progressed on imatinib at a dose of 400 mg/day.

The objectives of this review will help facilitate decision-making on the most appropriate treatment(s) for patients with unresectable and/or metastatic GIST who have progressed on imatinib at a dose of 400 mg/day, by:

• conducting a systematic review of the evidence available on the clinical effectiveness of imatinib at dosages of 600 or 800 mg/day compared with sunitinib and/or BSC

• conducting a systematic review of the cost-effectiveness of imatinib at dosages of 600 or 800 mg/day compared with sunitinib and/or BSC

• analysing available outcome data for particular subgroups of interest (e.g. patients with different KIT mutations) in order to establish any differences in clinical effectiveness for specific groups

• developing an economic model to compare the cost-effectiveness and cost–utility of imatinib at a dose of 600 or 800 mg/day with those of sunitinib (within its recommended dose range) or BSC only.

This report contains reference to confidential information provided as part of the NICE appraisal process. This information has been removed from the report and the results, discussions and conclusions of the report do not include the confidential information. These sections are clearly marked in the report.

Methods for reviewing effectiveness

Results

Number of studies identified

We identified 3365 records from the primary searches for the review of clinical effectiveness. After title and abstract screening, 2441 articles were considered not to be relevant for this review and were excluded. The full-text papers of 924 records were obtained and screened. One hundred and twenty-three of these full-text papers were non-English language publications. In total, six full-text papers and 10 abstracts reporting four separate clinical trials and one additional retrospective cohort met our inclusion criteria. An additional 49 papers were retained for background information. The reasons for exclusion of assessed full-text papers are given in Table 1. A flow diagram of the screening process is outlined in Figure 1. Information on the reasons for excluding individual studies is provided in Appendix 5.

TABLE 1 - Reasons for exclusion of studies

Reason for exclusion	No. of studies excluded
Patient had resectable GIST	24
Outcomes not reported separately for patients with GIST	10
< 10 patients in relevant study population	46
Imatinib dose is 400 mg/day	13
No/insufficient data reported for escalated dose patients	65
No imatinib dose reported	84
No relevant interventions	15
Treatment not evaluated	11
No outcomes of relevance	10
Other reason	61
	339
Retained for background information	49
Review articles	169
Letter/editorial/correspondence/symposium articles/meeting reports/expert views/comments	117
Case study/case series < 10 patients	64
Non-English language exclusions	123
Not obtained	47
Total	908

FIGURE 1.

Flow diagram outlining the screening process for the review of clinical effectiveness.

Quality of the included studies

Results of the quality assessment for all four included full-text papers are summarised in Figure 2. No third party arbitration for quality assessment was required. The results of the quality assessment for each individual study are provided in Appendix 9. Three full-text studies assessed for quality assessment were included in the review because they provided crossover data on a subset of patients who were originally randomised to a dose of 400 mg/day, but progressed and received an escalated dose of either 600 mg/day39 or 800 mg/day. 41,44 The fourth study79 was assessed for quality because it included a retrospective analysis of a subgroup of a cohort of patients given treatment with imatinib at 400 mg/day. The subgroup were patients who received escalated doses of 600 mg/day and/or 800 mg/day after progression on the 400 mg/day dose.

FIGURE 2.

Quality assessment results summary.

As the study populations of interest were not the original randomised populations, but the crossover subgroup in three studies,39,41,44 and a subgroup of consecutively treated patients in the remaining study,79 quality was assessed using the checklist for non-randomised studies (detailed in Methods, above). Questions within this checklist that were specific to non-randomised comparative groups (i.e. Q6 and Q16) were not considered applicable to the crossover subset population included in our review, and were therefore not summarised (see Appendix 4).

However, two specific domains were assessed using the Cochrane Collaboration’s tool for assessing risk of bias, namely sequence generation and allocation concealment, as these would check for selection bias at trial level.

Sample definition and selection

In three studies39,41,44 the included subgroups of participants were randomised at trial level, but crossover patients were not randomly selected, and so it is unclear the extent to which this group can be considered representative of the relevant patient population (Q1). The other study provided inadequate information to allow judgement of the representativeness of the sample. 79 With regard to the randomisation process at trial level, the studies by Blanke et al. 41 and Zalcberg et al. 44 used methods that adequately generated the allocation sequence to avoid influence of confounding factors while Blanke et al. 39 did not report sufficient data on the randomisation process. In the study by Zalcberg et al. ,44 allocation to treatment was not concealed. Both the B222239 and S003341 studies by Blanke et al. reported inadequate information on allocation concealment. All four studies adequately described inclusion and exclusion criteria (Q2). To consider whether participants entered the study at a similar point in their disease progression, we looked at data on their performance status. Three of the studies39,41,79 involved participants whose performance status at the time of study entry was similar, while the study by Zalcberg et al. 44 included participants with different performance status at study entry (Q3), although most of the participants in all populations had a performance status of < 2, meaning they were ambulatory and awake for at least 50% of their waking hours. None of the studies undertook consecutive selection of patients (Q4). Data were collected prospectively in all of the four studies (Q5).

Description of the intervention

The intervention was adequately defined by all studies (Q7). However, no study provided sufficient data describing supervision of the intervention (Q8) and no information was provided describing the types of staff involved, or the facilities used (Q9).

Outcome assessment

The quality of all four studies was similar in terms of outcome assessment (Q10). None of the studies had considered all of the outcomes of interest, but all reported the objective response of escalated imatinib dosing in patients with GIST, while one41 reported OS and two41,44 measured PFS. The study by Park et al. 79 reported time to progression, and the study by Zalcberg et al. 44 was the only study that also reported adverse events for those on an escalated dose of imatinib. No study reported outcomes related to QoL.

All four studies used valid and reliable outcome measures (Q11), such as RECIST to assess objective response or Kaplan–Meier methods to estimate survival curves, minimising detection bias. Assessment of main outcomes was not blinded in any of the studies (Q12).

Follow-up and attrition bias

Follow-up was considered long enough to detect important effects on outcomes of interest in all but one study where follow-up information was not provided and so this was unclear79 (Q13). Information on those lost to follow-up was either not provided39 (and thereby likely to introduce bias) or not provided at a sufficient level of detail41,44,79 to judge whether those lost to follow-up would be likely to introduce bias (Q14 and Q15).

Performance of the analysis

For both studies by Blanke et al. ,39,41 important prognostic factors such as sex, performance status, neutrophils counts, etc., were investigated and multivariate analyses were performed at trial level but this was not carried out for the subset of patients who crossed over. Similarly, Park et al. 79 identified possible prognostic factors (but did not adjust for confounding factors during analysis). The study by Zalcberg et al. 44 also did not identify any prognostic factors or their effect on analyses, or adjust for confounding factors (Q17 and Q18). Hence we considered the quality of reporting ambiguous in terms of the performance of the analyses.

Assessment of effectiveness

Response

For imatinib at an escalated dose of 600 mg/day following progression at a dose of 400 mg/day, response is reported in the B2222 study by Blanke et al. 39 and the study by Park et al. 79 In the study by Blanke et al. ,39 the median follow-up at this time was 63 months (maximum 71 months), and, at that time, 43 patients had crossed over from 400 to 600 mg/day. Of these 43 patients, 11 (25.6%) showed either PR or stable disease (SD). However, it should be noted that one patient showed response only after further escalation from 600 to 800 mg/day. Some of the 43 patients who crossed over would have had an initial response to 400 mg/day before progression, as only 11 patients in the 400 mg/day arm showed a best response of PD. 39 Interim data for this study population are provided in the study by Demetri et al. ,38 where, after a median follow-up of 288 days (maximum 9 months), nine patients had crossed over, with one showing PR at that point, and two with SD. 38

In the study by Park et al. ,79 median follow-up was eight months (range 1.4–22.3 months) and, of the 12 patients who received an escalated dose of 600 mg/day of imatinib, five (41.7%) showed either PR or SD.

With regard to response data provided by the manufacturer, (CiC information has been removed). As a result, these data from the manufacturer’s submission were not used in our review.

For imatinib at a dose of 800 mg/day following progression at a dose of 400 mg/day, response data are available from the S0033 study by Blanke et al. ,41 the EORTC-ITG-AGITG trial by Zalcberg et al. 44 and the study by Park et al. 79 Of the crossover populations in the S003341 and EORTC trials44 (117 and 133 patients, respectively), three patients in each trial (i.e. six in total) had a PR, while 33 patients in the S0033 trial41 and 36 patients in the EORTC-ISG-AGITG trial44 had SD as a best response. This means that out of a total of 250 patients, 75 (30%) had a response after escalation from 400 mg to 800 mg/day.

Response information from the study by Park et al. 79 did not provide separate data for those with SD and those achieving PR. However, it did state that four out of the 12 patients (33.3%) receiving an escalated imatinib dose of 800 mg/day upon progression at the 400 mg/day dose achieved either PR or SD. 79

Some of the patients receiving dose-escalated imatinib to 800 mg/day would have had an initial response to the 400 mg/day dose, because only 42/345 patients (12.2%) in the S0033 trial 400-mg arm had a best/only response of PD (or ‘early death’),41 and in the study by Zalcberg et al. 44 this figure was 61/473 (12.9%). 42

Interim data for the EORTC-ISG-AGITG trial were provided for a data cut-off point of 7 December 2003, at which point there were 2/97 (2.1%) patients showing a PR, 30/97 (30.9%) patients with SD, and 65/97 (67.0%) patients with PD. 78 Interim data for the S0033 trial, also from December 2003, showed that there were 5/68 (7.4%) patients with PR, and 20/68 (29.4%) patients with SD, during crossover treatment with 800 mg/day of imatinib, following failure of treatment at 400 mg/day. 68

In addition, secondary analysis for the EORTC-ISG-AGITG trial in the study by Debiec-Rychter et al. 14 indicated, without stating the number of patients involved, that response following crossover was significantly more likely to occur in patients with wild-type GIST than with KIT exon 11 mutation (p = 0.0012), and response following crossover was also significantly more likely to occur in patients with KIT exon 9 mutation compared with exon 11 mutation (p = 0.0017). 14

No response data were provided for treatment with sunitinib at a dose of 50 mg/day (as part of a 4 weeks-on-treatment/2 weeks-off-treatment 6-week cycle), following progression on an imatinib dose of 400 mg/day.

Overall survival

For imatinib at an escalated dose of 600 mg/day following progression at a dose of 400 mg/day, OS data were not reported by Blanke et al. 39 (CiC information has been removed) for the B2222 trial.

For imatinib at a dose of 800 mg/day following progression at a dose of 400 mg/day, the EORTC-ISG-AGITG trial by Zalcberg et al. 44 did not report OS outcomes. However, the S0033 trial by Blanke et al. 41 reported relevant outcome data, and at the time of the analysis (median follow-up of 4.5 years) noted that 76/118 (64.4%) of patients had died. 41 Median OS was 19 months (95% CI 13 to 23 months) starting from the commencement of crossover. Interim data for the S0033 trial were also provided in the study by Rankin et al. ,68 which stated that median OS at December 2003 was 19 months. 68

(CiC information has been removed.)

(CiC information has been removed.)

TABLE 4 - (CiC information has been removed.)

(CiC information has been removed.)

(CiC information has been removed.)

TABLE 5 - (CiC information has been removed.)

For sunitinib, OS data were available for those on 50 mg/day of sunitinib who failed on a prior imatinib dose of ≤ 400 mg/day from two abstracts of the same trial, taken at different follow-up periods. 82,86 The data from the study by Reichardt et al. 82 were analysed after a median of four cycles. Median survival at this point was 93 weeks (95% CI 72 to 100 weeks) and 231/339 (68.1%) of patients were still alive. 82 The data from the report by Seddon et al. 86 were analysed after a median of 51 weeks (range 0.1–159 weeks). Median survival at that time was 90 weeks (95% CI 73 to 106 weeks) and 193/351 (55%) were still alive. 86 It should also be noted that further interim OS data were provided in another study by Seddon et al. ,85 but although the date of analysis is the same month as that reported by the studies by Reichardt et al. 82 and Rutkowski et al. ,83 the median OS reported differed, at 80.4 weeks (95% CI 60.3 to NA weeks), while the population who had failed on doses of imatinib of ≤ 400 mg/day was also less (307 patients). 85

It was possible to compare OS with an escalated dose of 800 mg/day, from the S0033 trial reported by Blanke et al. ,41 with that with sunitinib at a dose of 50 mg/day (provided in 4 weeks-on/2 weeks-off cycles of 6 weeks), for patients who had progressed on imatinib at a dose of 400 mg/day. Quarterly OS estimates for the sunitinib participants reported in a Kaplan–Meier chart by Seddon et al. 86 were obtained using the method proposed by Parmar et al. 73 and compared with OS estimates for the S0033 trial provided by the authors. The results are provided in Figure 3.

FIGURE 3.

Comparison of OS estimates for imatinib at 800 mg/day and sunitinib at 50 mg/day.

The study by Zalcberg et al. did not report information on OS and was therefore not included in the comparison in Figure 3. However, data are available from the (CiC information has been removed), and data from the study by Seddon et al. 86 on treatment with sunitinib are provided in Table 6.

TABLE 6 - Comparison of OS estimates for imatinib at 800 mg/day and sunitinib at 50 mg/day

NR, not reported

No. years elapsed	Seddon 200886 (n = 351)		(CiC information has been removed)
	Survival estimate	95% CI	(CiC information has been removed)	(CiC information has been removed)
1	0.684	0.626 to 0.741	(CiC information has been removed)	(CiC information has been removed)	(CiC information has been removed)
2	0.441	0.379 to 0.503	(CiC information has been removed)	(CiC information has been removed)	(CiC information has been removed)
3	0.200	0.140 to 0.261	(CiC information has been removed)	(CiC information has been removed)	(CiC information has been removed)
4	NR		(CiC information has been removed)	(CiC information has been removed)	(CiC information has been removed)

Disease-free survival

No data were reported for this outcome on account of no patient in any of the included studies having a complete response.

Progression-free survival

For imatinib at an escalated dose of 600 mg/day following progression at a dose of 400 mg/day, PFS data were not reported by Blanke et al. 39 (CiC information has been removed) for the B2222 trial.

For imatinib at an escalated dose of 800 mg/day following progression at a dose of 400 mg/day, data were reported for the S0033 trial by Blanke et al. ,41 and for the EORTC-ISG-AGITG trial by Zalcberg et al. 44

For the S0033 trial, at the time of the analysis, median follow-up of 4.5 years (54 months), 99/118 (83.9%) of the crossover cohort for whom data were available had progressed. 41 Median PFS was estimated to be 5 months (95% CI 2 to 10 months). Of the 99 patients who had PD or had died at the time of the analysis, 23/99 (23.2%) had progressed but were still alive. Interim data from this trial, at a data cut-off point of December 2003, gave median PFS to be 4 months following crossover, for 68 patients. 68

For the EORTC-ISG-AGITG trial, median follow-up was 25 months (maximum follow-up was 35 months), and, at that time, 108/133 (81.2%) of the crossover cohort with data available had progressed. Median PFS was 81 days. Sixty-seven patients (50.4%) had progressed or died within 3 months (Kaplan–Meier survival estimate 0.467). At 1 year, the Kaplan–Meier survival estimate was 0.181. 44

(CiC information has been removed.)

The estimates of PFS provided at 3-month intervals by the authors of the S0033 study,41 and available as a Kaplan–Meier chart in the published paper of this study by Blanke et al. ,41 were compared with PFS estimates at 3-month intervals that were measured from an enlarged copy of the plot of the Kaplan–Meier survival function estimate given in the paper by Zalcberg et al. 44 The number of events in each time period was then calculated using the method proposed by Parmar et al. ,73 corrected to ensure that the total number of patients censored was consistent with the number reported in the published paper. 44 For both trials the standard error of the survival function estimates was estimated from the quarterly numbers for events and patients at risk using Greenwood’s formula. Figure 4 shows the survival functions from each trial, together with 95% CIs for each.

FIGURE 4.

Kaplan–Meier plot for PFS with 800 mg/day imatinib.

A meta-analysis of these two survival curves was attempted, using the methods described in Arends et al. 92 However, no valid results could be achieved owing to the lack of data.

For sunitinib at a dose of 50 mg/day for a 6-week cycle, no progression data were available specifically for trial participants who had failed on a prior dose of imatinib at ≤ 400 mg/day.

Time to treatment failure

Data on the duration of response/time to treatment failure were available from the study by Park et al. ,79 which showed that, of the 12 patients who had their imatinib dose escalated to 600 mg/day following progression at the 400 mg/day dose, one patient died of a cause unrelated to both their disease and imatinib treatment, while the remaining 11 patients eventually progressed on imatinib treatment at the escalated dose after a median of 1.7 months (range 0.7–24.9 months).

For those receiving an escalated dose of 800 mg/day of imatinib following progression at an initial dose of 400 mg/day, data were available from the EORTC-ISG-AGITG trial showing that, of those who achieved PR or SD after crossover, the median duration of ‘stabilisation’ (i.e. PR or SD after crossover) was 153 days (range 37–574 days). 44 Interim data from this trial (7 December 2003 data cut-off) gave a median time to progression of 78 days. 78

For the sunitinib trial, the specific median treatment duration for those given sunitinib after failure on imatinib at a dose of ≤ 400 mg/day was not provided, but interim median treatment duration for the whole cohort was reported at 126 days (range 1–618), and at that time point (median follow-up not stated) it was noted that median treatment duration ‘did not significantly differ based on the dose of prior imatinib therapy (≤ 400 vs > 400 mg/day). 80

Health-related quality of life

No data were reported for this outcome by any of the included studies.

Adverse events

Data on adverse events were not reported for participants receiving an escalated dose of 600 mg/day of imatinib following progression at an initial dose of 400 mg/day.

For those receiving an escalated dose of 800 mg/day of imatinib following progression at an initial dose of 400 mg/day, data were available from the EORTC-ISG-AGITG trial reported by Zalcberg et al. ,44 and there was some information on dose reductions in the S0033 trial report by Dileo et al. 77

The number of discontinuations due to adverse events was not explicitly stated for the EORTC-ISG-AGITG trial44 reported in the study by Zalcberg et al. , but they did report that the vast majority of discontinuations (88.4%, i.e. approximately 86/97 withdrawals) were due to disease progression, suggesting that the maximum possible adverse event withdrawals possible would be 11.6% of all 97 withdrawals, i.e. 11 patients. Interim data for this trial at a December 2003 data cut-off point showed that there were two toxicity withdrawals at that time. 78

Data from this trial on specific adverse events following crossover are shown in Table 7 for those patients with 60 days’ follow-up data.

TABLE 7 - Adverse event data from the study by Zalcberg et al.44

Adverse event	No. with adverse event	Less severe after crossover (n, %)	More severe after crossover (n, %)	No. achieving new grade 3- to grade 4-level adverse event
Oedema	99	25/99 (25.3)	33/99 (33.3)	7
Skin rash	45	23/45 (51.1)	19/45 (42.2)	2
Fatigue	102	21/102 (20.6)	47/102 (46.1)	10 (p < 0.001)
Dyspnoea	30	8/30 (26.7)	14/30 (46.7)	1
Infection	20	9/20 (45.0)	9/20 (45.0)	1
Nausea	82	38/82 (46.3)	26/82 (31.7)	3
Leucopenia	56	25/56 (44.6)	16/56(28.6)	0
Neutropenia	49	30/49 (61.2)	13/49 (26.5)	0 (p = 0.002)
Thrombocytopenia	7	4/7 (57.1)	2/7 (28.6)	0
Anaemia	119	15/119 (12.6)	51/119 (42.9)	17 (p = 0.015)

A higher proportion of those with skin rash, nausea, leucopenia, neutropenia and thrombocytopenia had reduced severity from these effects following crossover to the 800 mg/day dose of imatinib, compared with the proportion who had increased severity from these effects following crossover (though, with the exception of neutropenia, these differences were not significant at the 0.05 level). The same proportion of people with infection had increased and decreased severity from this following crossover. For all other adverse events, a higher proportion of sufferers had increased severity from these effects than improvement, and in the case of anaemia and fatigue the increase in severity following crossover was significant at the 0.05 level. 44

Interim data reported by Zalcberg et al. 78 for this trial showed that 31% of patients (exact number not calculable) required a dose reduction (note: stated as ‘cumulative incidence’). No information was provided on the dose given following dose reduction.

Interim data for the S0033 trial reported by Dileo et al. 77 showed that, of the 77 patients who had crossed over from an imatinib dose of 400 to 800 mg/day at that time, 18 (23.3%) had at least one dose delay, and 12 (15.6%) had at least one dose reduction, due to oedema and rash. No information was provided on the dose given following dose reduction.

(CiC information has been removed.)

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TABLE 8 - (CiC information has been removed.)

TABLE 9 - (CiC information has been removed.)

For sunitinib at a dose of 50 mg/day for a 6-week cycle, no progression data were available specifically for trial participants who had failed on a prior dose of imatinib at ≤ 400 mg/day.

A summary of the results for all outcomes with the exception of adverse events is provided in Table 10.

TABLE 10 - Summary of results

All units of measurement for time have been converted into months by dividing by four for weeks, by dividing by 28 for days, and multiplying by 12 for years. All figures that were originally in units of measurement other than months are therefore approximate.

Drug/dose	Median follow-up (range): months	n (%) with PR or SD	Duration of response/time to treatment failure	Median OS (95% CI)	n (%) still alive	Median progression-free survival (95% CI)	n (%) progression free	Reference source
Sunitinib at 50 mg/day	4.5 (0–22.1)		Median treatment duration did not differ based on prior imatinib dose					Kang 200780
	< 6 ?			20.1 months (15.1 to N/A months)	?/307			Seddon 200785
	6			23.3 months (18–25 months)	231/339 (68.1)			Reichardt 200882
Imatinib at 600 mg/day	8	5/12 (41.6)	1.7 months (range 0.7–24.9 months)					Park 200979
Imatinib at 800 mg/day	8	4/12 (33.3)						Park 200979
Imatinib at 600 mg/day	9.5 (?–9)	3/9 (33.3)						Demetri 200238
Sunitinib at 50 mg/day	12 (0–39.8)			22.5 months (18.3–26.5 months)	193/351 (55)			Seddon 200886
Imatinib at 800 mg/day	< 25 (< ? to < 35)	32/65 (49.2)	2.8 months					Zalcberg 200478
	25 (?–35)	39/133 (29.3)	5.5 months (range 1.3–20.5 months)			2.9 months	25/133 (18.8)	Zalcberg 200544
	< 54	25/68 (36.8)		19 months (not stated)				Rankin 200468
	54	36/117 (30.8)		19 months (13–23 months)	42/118 (35.6)	5 months (2–10 months)	19/118 (16.1)	Blanke S003341
Imatinib at 600 mg/day	63 (?–71)	11/43 (25.6)						Blanke B222239
Imatinib at 800 mg/day		Significantly more likely to occur in patients with wild-type and exon 9 mutations than exon 11 mutations						Debiec-Rychter 200614

Systematic review of existing cost-effectiveness evidence

The purpose of the review of economic evaluation studies was to identify published studies and assess their quality and usefulness for comparisons of treatments of GISTs; inform the methodology of the proposed economic model; and identify data on the parameters of the proposed economic model (e.g. utilities for different health states, costs and epidemiological data).

Economic modelling

Model structure

The structure of the model was informed by the modelling studies identified as part of the systematic review of economic evaluations, the review of clinical effectiveness, and other existing evidence including previous NICE TARs. We have also drawn upon advice from health-care professionals within the research team in this regard.

The model was developed to compare the alternative treatment strategies for people with KIT (CD117)-positive unresectable and/or metastatic GISTs whose disease has progressed on treatment with imatinib at a dose of 400 mg/day or those whose treatment with imatinib has failed owing to intolerance. According to the scope for the review the treatment strategies to be compared in the models were:

1. treatment with an escalated dose of 600 mg/day, regulating symptoms with BSC

2. treatment with an escalated dose of 800 mg/day, regulating symptoms with BSC

3. treatment with sunitinib (within its recommended dose range), regulating symptoms with BSC

4. regulating symptoms with BSC only.

The assumed pathway of the model

We considered a range of different alternative pathways for patients who progressed on imatinib at a dose of 400 mg/day, which led to the creation of nine alternative pathways, and, following advice from our clinical advisers, we determined seven clinically plausible pathways (Figure 5). The model is based on these seven clinically plausible care pathways. Circles represent health states that individuals may return to, rectangles represent health states during which treatment is administered, and the arrows show the possible directions in which individuals could move at the end of each cycle, depending on the transition probabilities. The states considered in the model were those thought to reflect care pathways for people with GIST. Patients entering the pathways are those who failed on imatinib 400 mg/day. The alternative treatments considered were dose T1 = imatinib 600 mg/day, T2 = imatinib 800 mg/day, T3 = sunitinib (with recommended dose 50 mg/day) and BSC.

FIGURE 5.

Markov model for GIST patients who have failed with imatinib 400 mg/day.

A Markov model was developed to model these care pathways using Treeage Pro 2009 (TreeAge Software Inc., Williamstown, MA, USA). In this model, patients whose disease has progressed on treatment with imatinib at a dose of 400 mg/day or those whose treatment with imatinib has failed owing to intolerance enter one of the seven care pathways. Figure 6 is an illustrative example of the model structure for Path-4, where patients are treated with imatinib 600 mg/day, and if the disease progresses on this treatment the patients are treated with BSC. Appendix 12 illustrates the model for all seven pathways of alternative treatments.

FIGURE 6.

Example of model structure for care pathway Path-4 (imatinib 600 mg/day – BSC).

Path-1 shows the patients with BSC treatment. It is assumed that the patients with BSC are still treated with imatinib and palliative care. Path-2 represents treatment options where escalated doses of imatinib (600 and 800 mg/day) and treatment with sunitinib are provided to the cohort of patients. All patients start the treatment with imatinib 600 mg/day. If they survive and respond to imatinib 600 mg/day then they will continue with the dose until they move to a state of stable condition with complete response or PR (CR/Stable IM 600). From this point, a proportion of patients will survive and continue to respond to treatment. Those who stop responding to imatinib 600 mg/day move to a state where they receive imatinib 800 mg/day (PD at IM 600). A proportion of patients will remain with the escalated dose of imatinib 800 mg daily (CR/Stable IM 800). If patients fail to respond on imatinib 800 mg daily, they are switched to treatment with sunitinib (PD with sunitinib). If they respond to sunitinib then they will continue with the treatment and move to a state of stable condition with complete response or PR (CR/Stable with sunitinib). From this point, a proportion of patients may continue to respond to the treatment and remain stable, or they may stop responding to sunitinib and receive BSC for the remainder of their life.

Path-3 represents treatment options through which an escalated dose of imatinib (imatinib 600 mg/day only) and treatment with sunitinib are provided. In this pathway, all patients also start the treatment with imatinib 600 mg/day (PD initial treatment IM 600). If they respond to imatinib 600 mg/day then they will continue with the dose and move to a state of stable condition with complete response or PR (CR/Stable IM 600). If a patient treated with imatinib 600 mg/day fails to respond, or ceases to respond, then instead of trying further dose escalation with imatinib they are switched to treatment with sunitinib (PD with sunitinib). If they respond to sunitinib they will continue with the treatment and move to a state of stable condition with complete response or PR (CR/Stable with sunitinib). Should they fail to respond to sunitinib or if at some point they cease to respond they continue with BSC for the remainder of their life.

In Path-4, all patients start the treatment with imatinib 600 mg/day and no switching to other treatments is considered. If they respond to imatinib 600 mg/day then they continue with this treatment until the GIST progresses or they die (CR/Stable IM 600). If at any point they do not respond to imatinib 600 mg/day they continue with BSC for the remainder of their life. This option has been considered as a treatment option in the model, although actual clinical practice may favour further escalation to 800 mg/day. Nevertheless, for this model, care pathways were developed with clinical advice on plausible pathways of care, some of which may be more typical of current practice than others.

The remaining care pathways are variants of earlier pathways. Path-5 is similar to Path-3 with respect to the combination of escalated dose of imatinib and sunitinib, the main difference in this case is that the escalated dose is imatinib 800 mg/day. Apart from this difference the pathways are identical. Path-6 is similar to Path-4. However, in this pathway the escalated dose is imatinib 800 mg/day instead of imatinib 600 mg/day. Path-7 is similar to Path-4. In this pathway, however, instead of being treated with imatinib 600 mg/day, patients receive sunitinib. Apart from this change, the care pathways are identical (see Appendix 12).

The care pathways chosen for our model are not exhaustive and do not include every single possible clinical intervention available to oncologists treating GIST after failure at 400 mg/day of imatinib, but the care pathways chosen reflect the scope of this research as agreed with NICE. Other possible treatments (e.g. surgery for those whose tumours become resectable following treatment with escalated doses of imatinib) were not considered.

Key assumptions of the modelling exercise

The key assumptions of the model are:

1. The time horizon of the model is 10 years, over which time all patients are expected to die, and the cycle length is 1 month.

2. The model assumes that patients entering a pathway will remain in a health state and on the treatment for one cycle only. If they respond and remain stable they continue on the treatment in the next cycle. If they do not respond but survive in the treatment arm they are considered to move to an escalated dose, move to another alternative (if allowed by a treatment pathway) or continue with BSC for the remaining time horizon of the model.

3. The model assumes that the probabilities of progressing and dying do not change over time. This assumption was made because of the limited data available.

4. The utilities of the health outcome from treatment with imatinib 600 mg/day, imatinib 800 mg/day and sunitinib are assumed to be the same. This assumption was made because of the limited data available.

5. All patients failing or not responding to the treatment in any of the treatment arms of the model continue with BSC for the remainder of the model time horizon or until they die, and are assumed to derive the same utility as from the health state of progression. Owing to lack of data, time-dependent changes in transition rates of response were not built into the model.

Results

Base-case analysis

Table 16 shows the mean estimates of cost and effectiveness of the seven alternative treatment strategies modelled. As this table shows, effectiveness has been reported in two ways: life-years and QALYs. Path-4, imatinib 600 mg/day has an incremental cost per QALY that is < £30,000 compared with Path-1, BSC. The only other non-dominated or non-extendedly dominated strategy is Path-2, imatinib 600 to imatinib 800 mg/day to sunitinib. However, in this case the incremental cost per QALY (compared with the next most costly option of Path-4, imatinib 600 mg/day) is in excess of £40,000.

TABLE 16 - Base-case analysis and incremental cost–utility of the alternative treatment pathways

Strategies	Cost (£)	Incremental cost (£)	Life-years	Incremental life-years	QALYs	Incremental QALYs	Incremental cost per QALY (£)
Path-1 BSC	92,811		4.154		2.397
Path-7 Sunitinib	96,688	3877	3.716	(Dominated)	2.411	0.014	272,365
Path-4 Imatinib 600 mg	147,060	50,372	5.211	1.057	4.256	1.845	27,304
Path-3 Imatinib 600 mg to sunitinib	149,200	2139	5.032	Dominated	4.286	0.030	71,723
Path 6 Imatinib 800 mg	153,901	4702	4.506	Dominated	3.635	–0.651	Dominated
Path-5 Imatinib 800 mg to sunitinib	155,828	6628	4.336	Dominated	3.659	–0.627	Dominated
Path-2 Imatinib 600 mg to 800 mg to sunitinib	172,152	22,953	5.278	0.067	4.803	0.517	44,359
With dominated and extendedly dominated options removed
Path-1 BSC	92,811		4.154		2.397
Path-4 Imatinib 600 mg	147,060	54,249	5.211	1.057	4.256	1.859	29,181
Path-2 Imatinib 600 mg to 800 mg to sunitinib	172,152	25,092	5.278	0.067	4.803	0.547	45,850

Of note is that in the base-case analysis treatment with sunitinib for those who failed with imatinib 400 mg/day (Path-7) was estimated to have a lower life expectancy than BSC but greater QALYs. The reason for this was that the estimates of survival for sunitinib were based upon limited non-randomised and non-comparative data (as was the case for all the other comparators). Hence, any comparison should be treated cautiously.

The finding that sunitinib was dominated by BSC when effectiveness was measured in life-years but not dominated when effectiveness was measured in QALYs illustrates the importance of the utility estimates used within the model. Again, such data were sparse and, particularly for sunitinib, do not reflect the potentially worse side effect profile. Other things remaining unchanged the inclusion of side effects would have reduced the QALYs obtained from pathways containing sunitinib and potentially led to Path-7 being dominated by BSC (at the very least the incremental cost per QALY would have increased from the £272,365 reported in Table 16).

The results reported in Table 16 are surrounded by considerable imprecision. One of the main sources of the imprecision in the analysis surrounds the clinical effectiveness data. Therefore, a partial probabilistic sensitivity analysis was conducted, with the imprecision surrounding response rates and mortality rates being characterised by beta distributions. Figure 7 shows the cost-effectiveness acceptability curve and illustrates that the pathway with the highest likelihood of being considered cost-effective when society’s willingness to pay for a QALY is less than approximately £25,000 is Path-1, BSC. When society’s willingness to pay for a QALY is between approximately £25,000 and £45,000 then Path-4, imatinib 600 mg/day, is most likely to be considered cost-effective. Beyond a threshold of approximately £45,000, Path-2, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, is most likely to be cost-effective.

FIGURE 7.

Cost-effectiveness acceptability curve for alternative treatments over the 10-year time horizon. Pathways with a low probability of being cost-effective over the range of willingness to pay for a QALY values considered have not been shown.

Sensitivity analysis

Uncertainty around the distributions used for mortality and response rates

The beta distributions used to generate Figure 7 potentially do not fully characterise the extent of the uncertainty surrounding the estimates of mortality and response used within the model. As noted in the previous section (see Probabilistic sensitivity analyses), this is because the data are used essentially as if they came from non-randomised, non-comparative sources, and hence any comparisons drawn may be highly biased. For this reason, in this sensitivity analysis uniform distributions were substituted for the beta distributions (Figure 8). It should be noted that these uniform distributions were assumed to be symmetrical around the point estimates used in the base-case analysis.

FIGURE 8.

Cost-effectiveness acceptability curve for alternative treatments over the 10-year time horizon assuming uniform distributions for mortality and response rates. Pathways with a low probability of being cost-effective over the range of willingness to pay for a QALY values considered have not been shown.

As Figure 8 illustrates, the basic pattern of the cost-effectiveness acceptability curve is the same as that depicted in Figure 7. At low threshold values for the willingness to pay for a QALY, Path-1, BSC, is still the most likely to be considered cost-effective. However, Path-7, sunitinib, is more likely to cost-effective at low thresholds. It should be noted that even though the distributions surrounding mortality weights are very wide in this analysis sunitinib is still associated with a trend towards a slightly higher mortality rate than BSC. As previously noted this trend is based upon sparse and potentially unreliable data on the performance of sunitinib. At a threshold value of approximately £36,000 Path-3, imatinib 600 mg daily to sunitinib, has a similar probability of being considered cost-effective as Path-1, BSC, and Path-4, imatinib 600 mg/day. Between a threshold of £36,000 and £48,000, Path-4, imatinib 600 mg/day, is most likely to be cost-effective, and beyond that threshold value Path-2, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, is most likely to be cost-effective.

Uncertainty surrounding structure and methodological assumptions around distribution

Two different discount rates have been applied to costs and benefits to examine the sensitivity of the results to plausible changes in the discount rate (Table 17). At a 0% discount rate there is no change in the options that are dominated or extendedly dominated, and the incremental cost per QALY for Path-4, imatinib 600 mg/day, compared with Path-1, BSC, increases to £31,183. The incremental cost per QALY for Path-2, imatinib 600 mg/day to 800 mg/day to sunitinib, compared with Path-4, imatinib 600 mg/day, increases to £54,715.

TABLE 17 - Sensitivity around the discount rate and length of run

	Strategy	Cost (£)	QALYs	Incremental cost per QALY (£)
Base case, i.e. discount rates = 3.5% on cost and benefit; time horizon = 10 years	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	147,060	4.256	27,304
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	71,723
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.803	44,359
Sensitivity analysis 1, i.e. discount rates = 0% on cost and benefit; time horizon = 10 years	Path-1 BSC	93,137	2.706
	Path-7 Sunitinib	97,719	2.672	Dominated
	Path-4 Imatinib 600 mg	159,462	4.833	31,183
	Path-3 Imatinib 600 mg to sunitinib	163,601	4.859	Extendedly dominated
	Path 6 Imatinib 800 mg	165,641	4.087	Dominated
	Path-5 Imatinib 800 mg to sunitinib	169,210	4.105	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	195,193	5.486	54,715
Sensitivity analysis 2, i.e. discount rates = 6%; time horizon = 10 years	Path-1 BSC	92,614	2.209
	Path- 7 Sunitinib	96,007	2.254	Extendedly dominated
	Path-4 Imatinib 600 mg	139,473	3.908	27,593
	Path-3 Imatinib 600 mg to sunitinib	140,394	3.940	28,801
	Path 6 Imatinib 800 mg	146,627	3.360	Dominated
	Path-5 Imatinib 800 mg to sunitinib	147,542	3.387	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	158,271	4.392	39,480

When the discount rate is changed to 6%, the incremental cost per QALYs for the non-dominated strategies falls compared with the base-case analysis. The key change is that Path-3, imatinib 600 mg/day to sunitinib, is no longer extendedly dominated by Path 4, imatinib 600 mg/day. Furthermore, the incremental cost per QALY for this comparison is < £30,000. Overall, the sensitivity analysis around discount rates illustrates that the results are sensitive to the choice of discount rate.

Table 18 reports the results of the sensitivity analysis around the time horizon of the model. When the time horizon is reduced to 6 years (base case = 10 years) the incremental cost per QALYs associated with the non-dominated options increases slightly. When the time horizon increases, the incremental cost per QALY for Path-4, imatinib 600 mg/day, compared with Path-1, BSC, increases slightly. The incremental cost per QALY for Path-2, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, compared with Path-4, imatinib 600 mg/day, is virtually unchanged.

TABLE 18 - Sensitivity around the time horizon of the model

	Strategy	Cost (£)	QALYs	Incremental cost per QALY (£)
Base case, i.e. discount rates = 3.5% on cost and benefit; time horizon = 10 years	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	147,060	4.256	27,304
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	71,723
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.803	44,359
Sensitivity analysis 3, i.e. discount rates = 3.5%; time horizon = 6 years	Path-1 BSC	73,246	1.960
	Path-7 Sunitinib	79,720	2.032	Extendedly dominated
	Path-4 Imatinib 600 mg	114,433	3.402	28,560
	Path-3 Imatinib 600 mg to sunitinib	117,729	3.455	Extendedly dominated
	Path-6 Imatinib 800 mg	126,750	3.017	Dominated
	Path-5 Imatinib 800 mg to sunitinib	129,873	3.066	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	131,848	3.758	48,969
Sensitivity analysis 4, i.e. discount rates = 3.5%; time horizon = 12 years	Path-1 BSC	98,464	2.510
	Path-7 Sunitinib	101,589	2.509	Dominated
	Path-4 Imatinib 600 mg	156,943	4.489	29,553
	Path-3 Imatinib 600 mg to sunitinib	158,421	4.507	Extendedly dominated
	Path-6 Imatinib 800 mg	161,295	3.790	Dominated
	Path-5 Imatinib 800 mg to sunitinib	162,637	3.803	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	183,961	5.093	44,736

Uncertainty surrounding transition probabilities of survival and response to treatment with imatinib 600 mg/day

The data available for imatinib given at a dose of 600 mg/day were sparse and what few data there were suggested a superior effectiveness compared with imatinib 800 mg/day. These data are (1) potentially unreliable because they are based upon non-randomised and non-comparative data and (2) potentially counterintuitive (in a direct comparison would we expect imatinib 800 mg/day to perform worse than imatinib 600 mg/day?). Therefore, in this sensitivity analysis it was assumed that the mortality and response to treatment with imatinib 600 mg/day was the same as that with imatinib 800 mg/day.

As Table 19 shows the incremental cost per QALY for Path-4, imatinib 600 mg/day, compared with Path-1, BSC, falls. This is because there is a reduction in the cost of medications as the probabilities that patients die or make the transition to BSC increases, which more than compensates for the fall in QALYs. The QALYs associated with Path-3, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, fall but the incremental cost per QALY compared with Path 4, imatinib 600 mg/day, is virtually unchanged.

TABLE 19 - Changes to mortality and response rates

	Strategy	Cost (£)	QALYs	Incremental cost per QALY (£)
Base case	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	147,060	4.256	27,304
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	71,723
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.803	44,359
Sensitivity analysis 5: survival rate and response rate to imatinib 600 mg treatment same as that with imatinib 800 mg	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	126,074	3.635	24,019
	Path-3 Imatinib 600 mg to sunitinib	128,001	3.659	80,476
	Path-2 Imatinib 600 to 800 mg to sunitinib	149,703	4.145	44,603
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 to sunitinib	155,828	3.659	Dominated
Sensitivity analysis 6: survival rate for BSC = 0.02349	Path-1 BSC	65,412	1.729
	Path-7 Sunitinib	77,669	1.954	Dominated
	Path-4 Imatinib 600 mg	137,060	4.022	31,239
	Path-3 Imatinib 600 mg to sunitinib	142,643	4.134	Extendedly dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	144,349	3.411	Dominated
	Path-6 Imatinib 800 mg	149,517	3.512	Dominated
	Path-5 Imatinib 800 to sunitinib	170,340	4.762	44,603

As noted in Data requirements and model inputs (above), the two sources106,107 of mortality data that we have used for BSC were chosen because these studies had larger sample sizes and longer median follow-up times (Appendix 13). We conducted sensitivity analysis using different sources of mortality data for BSC, i.e. using a pooled mortality estimate of 19.8% that is based on survival estimates from Pierie et al. ,107 Dougherty et al. 112 and Artyan et al. 113 The monthly mortality rate would be higher (0.02349) than what we have used in the base case (0.014627). As mortality for BSC increases, the cost and QALYs for the pathways fall because BSC is part of each pathway. As a consequence the incremental cost per QALYs do not change greatly although all slightly increase compared with less costly but less effective pathways because the increase in mortality for BSC has proportionately a greater effect on costs than on QALYs.

Uncertainty surrounding utility values

The sensitivity of a lower and higher value of utility for the health status of disease progression was examined. In this analysis the lower value was 0.52 and a higher utility value for those patients who progressed with GIST of 0.712 was assumed instead of 0.577, as was used in the base case (Table 20). Reducing the utility value increased the QALYs for treatments that had higher probabilities of response. The incremental cost per QALY for Path-4, imatinib 600 mg/day, compared with Path-1, BSC, slightly falls and the incremental cost per QALY for Path-2, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, compared with Path-4, imatinib 600 mg/day, falls to approximately £40,000.

TABLE 20 - Sensitivity analysis around the utility assumed for disease progression

	Strategy	Cost (£)	QALYs	Incremental cost per QALY (£)
Base case: utility of progressive state = 0.577	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	147,060	4.256	27,304
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	71,723
	Path 6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.803	44,359
Sensitivity analysis 6: utility of progressive state = 0.52	Path-1 BSC	92,811	2.160
	Path-7 Sunitinib	96,688	2.242	Extendedly dominated
	Path-4 Imatinib 600 mg	147,060	4.158	27,156
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.219	34,911
	Path 6 Imatinib 800 mg	153,901	3.543	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.596	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.782	40,759
Sensitivity analysis 7: utility of progressive state = 0.712	Path-1 BSC	92,811	2.958
	Path-7 Sunitinib	96,688	2.812	Dominated
	Path-4 Imatinib 600 mg	147,060	4.488	35,440
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.444	Dominated
	Path 6 Imatinib 800 mg	153,901	3.853	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.808	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.853	68,837

Conversely, increasing the utility associated with PD reduced the opportunity for pathways that are clinically more effective to generate additional QALYs. As a consequence, in this sensitivity analysis the incremental cost per QALYs for the non-dominated pathways increase.

Uncertainty surrounding the cost of imatinib and sunitinib

In this set of sensitivity analyses reductions in the cost of imatinib 600 mg/day, imatinib 800 mg/day and sunitinib are explored (Table 21). Over most of these sensitivity analyses the pathways that are dominated or are extendedly dominated do not change. As would be expected reducing the costs of each medication individually reduces the cost of pathways involving that medication. Over all these sensitivity analyses there are only relatively modest changes in the ICERs reported. One of the more substantive changes is that when the cost of sunitinib is reduced, Path-7, sunitinib, becomes the least costly option. This is primarily because this pathway uses potentially unreliable data on mortality for sunitinib which means that patients on this pathway do not survive long enough to incur higher costs.

TABLE 21 - Sensitivity around the costs of imatinib and sunitinib

	Strategy	Cost (£)	QALYs	Incremental cost per QALY (£)
Base case: Imatinib 600 mg £2406 Imatinib 800 mg $3208 Sunitinib £3138.8	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	272,365
	Path-4 Imatinib 600 mg	147,060	4.256	27,304
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	71,723
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	172,152	4.803	44,359
Sensitivity analysis 8 (change in imatinib 600 mg price): Imatinib 600 mg £2005 Imatinib 800 mg $3208.16 Sunitinib £3138.8	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	Extendedly dominated
	Path-4 Imatinib 600 mg	130,272	4.256	20,150
	Path-3 Imatinib 600 mg to sunitinib	132,412	4.286	Extendedly dominated
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	155,364	4.803	45,850
	Path-5 Imatinib 800 mg to sunitinib	155,828	3.659	Dominated
Sensitivity analysis 9 (change in imatinib 800 mg price): Imatinib 600 mg £2406 Imatinib 800mg $2807 Sunitinib £3138.8	Path-1 BSC	92,811	2.397
	Path-7 Sunitinib	96,688	2.411	Extendedly dominated
	Path-6 Imatinib 800 mg	139,988	3.635	Extendedly dominated
	Path-5 Imatinib 800 mg to sunitinib	141,915	3.659	Extendedly dominated
	Path-4 Imatinib 600 mg	147,060	4.256	29,181
	Path-3 Imatinib 600 mg to sunitinib	149,200	4.286	Extendedly dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	166,000	4.803	34,609
Sensitivity analysis 10 (change in sunitinib price): Imatinib 600 mg £2406 Imatinib 800mg $3208.16 Sunitinib £2092	Path-7 Sunitinib	87,533	2.411
	Path-1 BSC	92,811	2.397	Dominated
	Path-3 Imatinib 600 mg to sunitinib	144,524	4.286	30,400
	Path-4 Imatinib 600 mg	147,060	4.256	Dominated
	Path-5 Imatinib 800 mg to sunitinib	151,560	3.659	Dominated
	Path-6 Imatinib 800 mg	153,901	3.635	Dominated
	Path-2 Imatinib 600 to 800 mg to sunitinib	170,364	4.803	49,940

Summary

The systematic review of economic evaluations reported in this chapter was not especially informative. This was anticipated at the outset and hence an economic modelling exercise was planned. The modelling exercise compared alternative treatment pathways for patients with unresectable GIST who failed to respond to imatinib 400 mg/day. Over almost all the sensitivity analyses Path-1, BSC, is the least costly and least effective intervention. Similarly, Path-4, imatinib 600 mg/day, typically has an incremental cost per QALY that is less than £30,000 compared with Path-1, BSC. Path-2 (imatinib 600 mg/day to imatinib 800 mg/day to sunitinib) is the only other pathway which is not dominated or extendedly dominated over most of the analyses conducted. However, in this case the incremental cost per QALY (compared with the next most costly option – Path-4: imatinib 600 mg/day) tends to be in excess of £40,000.

When society’s willingness to pay for a QALY is less than approximately £25,000 Path-1, BSC, is the most cost-effective. When society’s willingness to pay for a QALY is between approximately £25,000 and £45,000 then Path-4, imatinib 600 mg/day, is most likely to be considered cost-effective. Beyond a threshold of approximately £45,000, Path-2, imatinib 600 mg/day to imatinib 800 mg/day to sunitinib, is most likely to be cost-effective.

The results of the economic analysis are based upon sparse data that are potentially biased and are surrounded by considerable imprecision. In particular, data for sunitinib and for imatinib 600 mg/day are the most suspect. The analysis has also not considered two main areas of uncertainty due to lack of data:

• The considerable uncertainty around the extrapolation from the sparse data on death and response rate and the impact of alternative assumptions about how probabilities of death and response change over time.

• Reductions in utility associated with adverse effects of treatment.

By assuming constant probabilities over time, death may be overestimated at earlier time points and underestimated at later stages of the time horizon of the model. The probability of death may increase over time as the disease progresses. Similarly the probability of non-response may increase over time and patients may have an increasing need for an escalated dose of imatinib, or sunitinib. The assumption of constant probability over time generally delays the transition to patients’ deaths. This means that our analysis has a bigger impact on the most effective treatments. These treatments will also incur high treatment costs over a longer period. The net impact of these two changes on cost-effectiveness is unclear.

The net impact of adjusting scores for adverse effects is also uncertain but it might be expected that it will reduce the QALYs associated with each medication and, although there are limited data available from the systematic review of clinical effectiveness, this reduction may be greater for pathways involving sunitinib because its adverse effect profile is believed to be worse than that of imatinib. 111

Owing to sparse data for this analysis, few data were available on the utility values for defined disease states in the model. Furthermore, the disease states selected in the model may not be complete and exhaustive as data on alternative plausible disease states were not available. Sensitivity analysis explored uncertainty in key parameter estimates but clearly this does not investigate the influence of structural assumptions such as the limited number of disease states chosen for the modelling. A more sophisticated model would have allowed further sensitivity analysis but without at least some data to guide assumptions we would have needed to identify threshold values for many individual parameters and combinations of parameters. This would have resulted in a substantially expanded economics chapter reporting extensive speculative results that would have been very difficult to interpret.

A further factor not considered by the economic model was the cost-effectiveness of treatment for those with specific gene mutations. Again this was not addressed owing to lack of data, and as there were also no data available to assess the impact of plasma monitoring on the study population of interest, this was also not considered by the economic model.

Finally, the economic evaluation has assumed that patients who move on to BSC remain on treatment to prevent tumour flare. This has the impact of increasing the cost of BSC. It is further assumed that there is no impact on effectiveness (the implicit assumption is that discontinuing the medication would reduce life expectancy). Within the analysis it has been assumed that all patients on BSC or moving on to BSC after failing to respond on a medication would receive imatinib 400 mg/day. This assumption appears reasonable for Path-1, BSC, but may not be appropriate for the other pathways where patients would move on to BSC after failing to respond on an escalated dose of imatinib or on sunitinib. Should these patients continue with the last active medication that they received then costs, and incremental costs per QALY, would increase.

Statement of principal findings

Strengths and limitations of the assessment

In terms of strengths, the review of the evidence base was detailed and thorough. It was unclear from the information provided in a substantial number of abstracts whether the studies met the inclusion criteria and full-text papers for all of these reports were obtained and assessed. Non-English language studies were not excluded. Authors were contacted in an attempt to obtain additional information concerning their studies. For the review of economic evaluations, a rigorous systematic approach was adopted. The economic model considered a large number of plausible alternative treatments and also incorporated both probabilistic and deterministic estimates of cost effectiveness. The former was limited to clinical effectiveness parameters but this limitation was chosen specifically to draw attention to the uncertainties surrounding these data.

In terms of limitations, there was a dearth of evidence available on the specific population of interest, despite the overall large evidence base on the treatment of GISTs with imatinib or sunitinib. The quality of reporting of dose information in reports of imatinib or sunitinib for GISTs was poor and the data on the population of interest for the studies that were included were non-randomised, non-comparative and therefore observational. Therefore, lack of quality data, as well as lack of data itself, severely limited both assessments of clinical effectiveness and cost-effectiveness.

There was also a lack of evidence on QoL outcomes, which may be of fundamental importance to patients given the potentially palliative nature of treatment following progression, and there was also a lack of evidence on BSC. This is important as since the development of imatinib and sunitinib, it no longer represents the only treatment option for those with unresectable/metastatic disease. There was little evidence on response to escalated doses of imatinib based on mutational status, specifically for those who had already failed on an initial imatinib dose of 400 mg/day. It was also not possible to account for the effects of required dose interruptions and reductions, or the effects of sunitinib on those intolerant to imatinib, owing to the lack of available data. This lack of data also prevented comparative analysis of adverse events between the intervention and comparator treatments.

For sunitinib, it was also necessary to assume that the vast majority of those receiving sunitinib after imatinib treatment at ≤ 400 mg/day had actually received imatinib at 400 mg/day, which may not be a valid assumption. However, it was not possible to confirm the validity of the assumption despite contacting the study authors (P Reichardt, HELIOS Klnikum Bad Saarow, Germany, 2010, personal correspondence). In addition, much of the evidence base for sunitinib generally relates to its use following the failure of escalated doses of imatinib rather than failure on 400 mg/day, suggesting that the role of sunitinib is seen more as a third-line treatment rather than a potential comparator to 600 mg/day or 800 mg/day imatinib treatment. This was highlighted by the manufacturer of imatinib in their submission for this technology appraisal, and is noted in Chapter 3 of this report.

For the economic model, sufficient sound comparative data for the different plausible treatments were not available, despite conducting an extensive review of relevant studies. This necessitated a number of simplifying assumptions being made with respect to the model and also the use of data that were potentially unreliable. The model assumes that patients entering a pathway will remain in that treatment for one cycle only if they do not respond and survive in the treatment arm. In these cases they are considered to move to the escalated doses, move to another alternative (if allowed by a treatment pathway) or continue with BSC for the remainder of the model time horizon or until they die. The care pathways considered in the economic model are not an exhaustive list of all possible treatment options available but represent plausible treatment scenarios. Some are likely to be more representative of clinical practice than others. Whilst additional clinical advice during the development of the care pathways might have increased the extent to which the chosen scenarios reflect true clinical practice, it may also have increased the level of complexity required within the model. Given the lack of robust data it was felt that a more sophisticated model would be difficult to populate.

Within the model, several simplifying assumptions had to be made for individual parameters. For example, it was necessary to consider the costs and utilities associated with BSC as consistent across all care pathways despite the fact that in clinical practice the costs of BSC may increase as an individual’s health deteriorates. Unfortunately, there were no data available to model how costs of BSC might increase and QoL might fall over time.

A further simplifying assumption was not to model the complications and side effects of therapy. This latter assumption was made owing to the very limited evidence available. This is coupled with the assumption made that the utility associated with stable response or progression did not vary between treatments. One impact of this assumption is that no utility decrement has been assumed for the arguably worse side effect profile of sunitinib. This means that pathways involving sunitinib may overestimate QALYs.

Perhaps a more important limitation is caused by the limited evidence base available. With respect to the clinical effectiveness data used to derive transition probabilities these data, as already noted, were based upon non-randomised, non-comparative data. Such data are potentially biased as well as being imprecise. In particular, it is worth noting that point estimates of death and response used within the model may be misleading, for example the point estimates used suggest that sunitinib has a higher mortality rate than BSC.

Uncertainties

For the assessment of clinical effectiveness:

• The diagnosis of GIST as stated in the final scope document was based on a positive KIT (CD117) test. However, this is not a perfect test and in a small (< 5%) number of cases a patient can have a GIST despite having a negative KIT (CD117) test. 4,7,25 More recent tests (e.g. PDGRFA and DOG1) may clarify diagnosis. However, the WHO classification of GI tumours recommends that a diagnosis of GIST should only apply to those patients testing positive for the KIT (CD117) protein.

• It was not possible to conduct any subgroup analysis for patients with particular mutations, or consider the methods used to identify response (e.g. FDG-PET or CT scanning), or possible factors related to the provision of dose-escalated imatinib in an adjuvant or neoadjuvant setting.

• It was not possible within the time frame of this review for sufficient information to be provided that would have enabled meta-analysis of outcomes for the 800 mg/day dose of imatinib. This evidence may have enabled more robust estimates of survival following dose escalation to 800 mg/day. However, the data would still be prone to bias (being taken from data from a non-randomised patient population) and uncertainty surrounding other parameters (e.g. BSC, sunitinib and imatinib at 600 mg/day) would still be likely to make the model difficult to interpret.

• Following progression, the proportion of patients subsequently progressing on escalated doses, who are kept on the study drug on the basis that progression of disease might be slower than if the patient were to be taken off the drug, is not known. It is also not clear whether there is a standard dose used for this purpose. Within the economic model it has been assumed that this would be the case (400 mg/day).

• This review only considered drug treatments that were licensed for patients with GISTs and did not consider other drugs that may be being used in the treatment of GISTs, or licensed drugs that are being used ‘off licence’ to treat GIST (e.g. imatinib at doses exceeding 800 mg/day, or sunitinib provided in a continuous daily dosing regime).

• Surgical interventions were also not considered even though surgery is an important treatment option for GIST patients, and even though those with unresectable disease may be eligible for surgery if their tumours become resectable following treatment with an escalated dose of imatinib. The role of emergency surgery as part of BSC was also not considered.

The economic model has also not considered three main areas of uncertainty due to lack of data:

• alternative assumptions about how probabilities of death and response change over time

• reductions in utility associated with side effects of treatment

• impact on cost-effectiveness for people with different gene mutations.

The impact of making alternative assumptions about how probabilities for death and response change is unknown but it is anticipated that the assumption of constant probabilities over time will exaggerate estimated life expectancy (and hence QALYs and cost) for all pathways. The net impact on relative cost-effectiveness is unclear as it depends upon the magnitude of any changes in both costs and QALYs that might occur.

A further uncertainty is the probability of death for BSC. No studies for this comparator met the inclusion criteria for the review. The only sources available for this parameter were from studies published in the pre-imatinib era where the population could not have been exposed to a prior 400 mg/day dose of imatinib, and the proportion of the study populations with KIT-positive GIST was not known. With regard to the impact of this uncertainty on the economic model, it is reasonable to assume that if, for example, there was an increase in mortality for BSC, the costs and QALYs associated with each of the pathways would fall because BSC is included within each pathway.

The net impact of adjusting utility scores for side effects is also uncertain but it might be expected that it will reduce the QALYs associated with each medication and, although there are limited data available from the systematic review of effectiveness, this reduction may be greater for pathways involving sunitinib because its side effect profile is believed to be worse than that of imatinib.

A further factor not considered by the economic model was the cost-effectiveness of treating patients with specific gene mutations. Again this was not addressed owing to lack of data.

No studies looking at plasma monitoring met our inclusion criteria, but its potential, along with that of mutation testing, as an early predictor of the need for escalated imatinib dosing may have implications for both the costs and effects of escalated doses, because it may allow the identification of those people who are expected to respond better to escalated doses quickly and hence they may be given escalated doses immediately rather than waiting for progression to occur at the 400 mg/day dose. If either of these practices become widely adopted within the NHS then the evidence on the effect of imatinib dose escalation following progression at the standard 400 mg/day dose will become less relevant to clinical practice. Should mutation testing and plasma monitoring allow the tailoring of dose escalation then we might expect the benefits to those who receive therapy to be increased, particularly at earlier stages of treatment (although this also means that there may be fewer remaining treatment options following failure at the escalated dose). Costs would also increase owing to both the cost of mutation testing or plasma monitoring, and also the costs of escalated doses that are incurred earlier. The net impact of this on cost-effectiveness is unclear.

Finally, the economic evaluation has assumed that patients who move on to BSC still receive medication to prevent tumour flare. This has the impact of increasing the cost of BSC. It is further assumed that there is no impact on effectiveness (the implicit assumption is that discontinuing the medication would reduce life expectancy). Within the analysis it has been assumed that all patients on BSC or moving on to BSC after failing to respond to a medication would receive imatinib 400 mg/day. This assumption appears reasonable for Path-1, BSC only, but may not be appropriate for the other pathways where patients would move on to BSC after failing to respond to an escalated dose of imatinib, or on sunitinib. Should these patients continue with the last active medication that they received then costs, and incremental costs per QALY, would increase.

Implications for service provision

• There was very limited evidence available from very few studies on the effects of escalated doses of imatinib 600 mg/day and 800 mg/day or treatment with sunitinib for people with unresectable and/or metastatic GIST, whose disease had progressed on the 400 mg/day dose. The evidence that was available was essentially observational in nature and subject to the biases associated with such data, consisting mostly of reporting of subgroups of patients in RCTs that were not designed to assess the effects of dose escalation.

• The limited evidence base suggests that around one-third of patients with unresectable and/or metastatic GIST who have failed on a dose of 400 mg/day may show response or SD with escalated doses of imatinib, and those who do respond may have a reasonable chance of maintaining this response over a longer period of time than would otherwise have been the case.

• For all patients receiving either dose-escalated imatinib or sunitinib, the median OS, where reported, was < 2 years.

• There is a need to interpret all results from the economic model with caution owing to the limitations of the evidence base. The results themselves indicate that should society’s threshold for willingness to pay be less than £25,000 per QALY a pathway of BSC only has the highest probability of being cost-effective. Between a threshold of £25,000 and £45,000 provision of an escalated dose of imatinib would be most likely to be cost-effective. Above a threshold of £45,000 a pathway of escalated doses of imatinib followed by sunitinib, if necessary, would be most likely to be cost-effective.

• In terms of policy-making, the results of this review and economic model show that the current evidence available on the effectiveness of imatinib dose escalation for GIST patients following progression on the standard 400 mg/day dose is characterised by such a high degree of uncertainty that, in the authors’ opinion, it would be inappropriate to conclude that dose escalation of imatinib would be a cost-effective strategy for the NHS.

Recommendations for research

Further evidence is needed in order to provide a comprehensive assessment of the effectiveness and cost-effectiveness of the alternative treatments for patients with GIST who fail on or become resistant to imatinib 400 mg/day. Ideally, such data would come from RCTs involving patients who progress on 400 mg/day of imatinib, where patients are randomised to 600 mg/day imatinib, 800 mg/day imatinib or sunitinib, or to remain on 400 mg/day imatinib. However, such a study may be difficult to organise, as neither patients nor practitioners may be in equipoise. Dose escalation appears to be used within the NHS already and hence health-care professionals may not find it acceptable that their patients could be randomised to ‘BSC’. Therefore, alternative quasi-experimental or observational designs should be considered but with sufficient focus on understanding and controlling for selection biases.

The pathways most likely to be cost-effective at thresholds society might be willing to pay and hence potentially the most useful to assess would be dose escalation with imatinib and dose escalation with imatinib followed by sunitinib if necessary. Such studies should as a matter of course include an economic evaluation and measurement of health-state utilities (where there is currently a dearth of evidence for each of the relevant health states for GIST patients), and would need to measure outcomes over a sufficiently long time period to capture the main impact on costs and outcomes. Where possible further studies should also report outcomes for subgroups of patients with specific KIT mutations.

With respect to costs, should further comparative studies be conducted, estimates of the usage of health services might usefully be collected. A wider perspective on the consideration of costs might also be informative, for example costs that fall on PSS (which would be relevant for NICE to consider) and costs for patients and their families (which goes beyond NICE’s reference case).

Contributions of authors

Jenni Hislop (Research Fellow) and Pawana Sharma (Research Fellow) screened the search results for clinical effectiveness, assessed full-text studies for inclusion, and undertook data extraction and quality assessment. Jenni Hislop drafted the chapters of the report other than the background and cost-effectiveness chapters, and coordinated the review. Pawana Sharma contributed to the chapter on clinical effectiveness and the appendices. Graham Mowatt (Senior Research Fellow) and Luke Vale (Professor of Health Technology Assessment) commented on drafts. Zahidul Quayyum (Research Fellow) screened the search results on cost-effectiveness, undertook data extraction and quality assessment, drafted the chapter on cost-effectiveness and developed the economic model, supervised by Luke Vale. Russell Petty (Clinical Senior Lecturer in Medical Oncology) drafted the background chapter, and provided expert advice on clinical aspects of the review. David Jenkinson and Andrew Elders (Statisticians) contributed to the data analysis section of the assessment of clinical effectiveness and conducted the statistical analysis. Cynthia Fraser (Information Specialist) developed and ran the search strategies, obtained papers and formatted the references. All authors assisted in preparing the manuscript and commenting on drafts. Graham Mowatt is guarantor.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

MEDLINE (2000 – September, week 3, 2009), EMBASE (2000–9, week 39), MEDLINE In-Process (25 September 2009)

SCI (2000 – 26 September 2009), BIOSIS (2000 – 24 September 2009), ISI Proceedings (2000 – 26 September 2009)

CINAHL (September 2009)

Cochrane Library Issue 3, 2009 [Cochrane Central Register of Controlled Trials (CENTRAL) and CDSR]

DARE and HTA Databases (October 2009)

Health Management Information Consortium (September 2009)

Clinical Trials (September 2009)

CCT (September 2009)

WHO International Clinical Trials Registry Platform (ICTRP) (September 2009)

Clinical Study Results Database (September 2009)

Association of the British Pharmaceutical Industry (ABPI) (September 2009)

International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) (September 2009)

Conference proceedings

Resectable GIST (n = 24)

Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 2007;13:170–81.

Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182–90.

Aparicio T, Boige V, Sabourin JC, Crenn P, Ducreux M, Le Cesne A, et al. Prognostic factors after surgery of primary resectable gastrointestinal stromal tumours. Eur J Surg Oncol 2004;30:1098–103.

Besana-Ciani I. Outcome and long term results of surgical resection for gastrointestinal stromal tumors (GIST). Scand J Surg 2003;92:195–9.

Bolukbasi H, Nazli O, Tansug T, Bozdag AD, Isgiider AS, Yaman I, et al. Gastrointestinal stromal tumors (GISTs): analysis of 20 cases. Hepatogastroenterology 2006;53:385–8.

Bucher P, Villiger P, Egger JF, Buhler L, Morel P. Results of primary surgical treatment of gastrointestinal stromal tumors. Gastroenterology 2004;126(Suppl. 2):58.

Date RS, Stylianides NA, Pursnani KG, Ward JB, Mughal MM. Management of gastrointestinal stromal tumours in the imatinib era: a surgeon’s perspective. World J Surg Oncol 2008;6:77–81.

Goh B, Chow P, Chuah K, Yap W, Foo K, Wong W. Pathological, radiological and PET scan response of gastrointestinal stromal tumors after neoadjuvant treatment with imatinib mesylate: a review of 37 cases. Ann Oncol 2006;17(Suppl. 6):101–2.

Gupta M, Sheppard BC, Corless CL, MacDonell KR, Blanke CD, Billingsley KG. Outcome following surgical therapy for gastrointestinal stromal tumors. J Gastrointest Surg 2006;10:1099–105.

Hou YY, Grabellus F, Weber F, Zhou Y, Tan YS, Li J, et al. Impact of KIT and PDGFRA gene mutations on prognosis of patients with gastrointestinal stromal tumors after complete primary tumor resection. J Gastrointest Surg 2009;13:1583–92.

Jindal S, Singhal D, Kakodkar R, Gupta S, Soin A, Chaudhary A, et al. Management of gastrointestinal stromal tumors: a single center experience in the pre-imatinib era. J Gastroenterol Hepatol 2008;23:A162–3.

McAuliffe JC, Hunt KK, Lazar AJ, Choi H, Qiao W, Thall P, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol 2009;16:910–19.

Machado-Aranda D, Malamet M, Chang YJ, Jacobs MJ, Ferguson L, Silapaswan S, et al. Prevalence and management of gastrointestinal stromal tumors. Am Surgeon 2009;75:55–60.

Mudan SS, Conlon KC, Woodruff JM, Lewis JJ, Brennan MF. Salvage surgery for patients with recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Cancer 2000;88:66–74.

Nieto EA. Gastrointestinal stromal tumors: experience in 49 patients. Clin Translat Oncol 2006;8:594–8.

Nikfarjam M, Kimchi E, Shereef S, Gusani NJ, Jiang Y, Liang J, et al. Surgical outcomes of patients with gastrointestinal stromal tumors in the era of targeted drug therapy. J Gastrointest Surg 2008;12:2023–31.

Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era: a population-based study in western Sweden. Cancer 2005;103:821–9.

Nishida T. Phase II trial of adjuvant imatinib mesylate after resection of localized primary high risk GIST. Eur J Cancer 2009;7:S594.

Nunobe S, Sano T, Shimada K, Sakamoto Y, Kosuge T. Surgery including liver resection for metastatic gastrointestinal stromal tumors or gastrointestinal leiomyosarcomas. Jpn J Clin Oncol 2005;35:338–41.

Perez EA, Gutierrez JC, Jin X, Lee DJ, Rocha-Lima C, Livingstone AS, et al. Surgical outcomes of gastrointestinal sarcoma including gastrointestinal stromal tumors: a population-based examination. J Gastrointest Surg 2007;11:114–25.

Rutkowski P, Nowecki Z, Nyckowski P, Dziewirski W, Grzesiakowska U, Nasierowska-Guttmejer A, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006;93:304–11.

Rutkowski P, Nowecki ZI, Michej W, Debiec-Rychter M, Wozniak A, Limon J, et al. Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor. Ann Surg Oncol 2007;14:2018–27.

Sujendran V, Fearnhead N, De Pennington N, Warren BF, Maynard ND. Proposals for the management of gastrointestinal stromal tumours of the stomach. Surgeon 2007;5:149–53.

Zhan WH. Efficacy and safety of adjuvant post-surgical therapy with imatinib. J Clin Oncol 2007;25(18S):Abstract 10045.

Outcomes not reported separately for patients with GIST (n = 10)

Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:2006–13.

Billemont B. Scrotal cutaneous side effects of sunitinib. N Engl J Med 2008;359:975–6.

Chugh R, Wathen JK, Maki RG, Benjamin RS, Patel SR, Myers PA, et al. Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a Bayesian hierarchical statistical model. J Clin Oncol 2009;27:3148–53.

Fraunfelder FW, Solomon J, Druker BJ, Esmaeli B, Kuyl J. Ocular side-effects associated with imatinib mesylate [Gleevec (R)]. J Ocul Pharmacol Ther 2003;19:371–5.

Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, et al. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res 2008;14:2717–25.

Kaneko T, Goto S, Kushima Y, Miyamoto Y, Eriguchi M, Nieda M, et al. A report of three patients treated with immunocell therapy with imatinib mesylate. Anticancer Res 2004;24:3303–9.

Oudard S, Negrier S, Ferrero JM, Gravis G, Blay JY, Le Cesne A, et al. Safety profile of single-agent sunitinib malate from the French Temporary Authorization for Use program (Cohort ATU) in metastatic renal cell carcinoma (MRCC) after failure of treatment with cytokines and gastrointestinal stromal tumor (GIST) patients after failure of imatinib mesylate treatment. Eur J Cancer 2007;5:S4526.

Polyzos A. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma and various other solid tumors. J Steroid Biochem Mol Biol 2008;108:261–6.

Radaelli F, Vener C, Ripamonti F, Iurlo A, Colombi M, Artoni A, et al. Conjunctival hemorrhagic events associated with imatinib mesylate. Int J Hematol 2007;86:390–3.

Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007;17:351–5.

Fewer than 10 patients in study population (n = 46)

Armbrust T. Does imatinib turn recurrent and/or metastasized gastrointestinal stromal tumors into a chronic disease? – Single center experience. Eur J Gastroenterol Hepatol 2009;21:819–23.

Banzo I, Quirce R, Martinez-Rodriguez I, Jimenez-Bonilla J, Sainz-Esteban A, Barragan J, et al. 18F FDG PET/CT in patients with gastrointestinal stromal tumors treated with imatinib mesylate. Eur J Nucl Med Mol Imaging 2007;34(Suppl. 2):298.

Bertolini V, Chiaravalli AM, Klersy C, Placidi C, Marchet S, Boni L, et al. Gastrointestinal stromal tumors – frequency, malignancy, and new prognostic factors: the experience of a single institution. Path Res Pract 2008;204:219–33.

Britten CD, Kabbinavar F, Hecht JR, Bello CL, Li J, Baum C, et al. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol 2008;61:515–24.

Bui BN. Trough imatinib plasma levels in patients treated for advanced gastrintestinal stromal tumors evidence of large interpatient variations under treatment with standard doses. J Clin Oncol 2008;26:Abstract 10564.

Bulusu VR, Basu BJ, Hatcher H, Parkinson C, Sherbourne K, Earl HM, et al. Imatinib mesylate (IM) in locally advanced and metastatic gastrointestinal stromal tumours (GISTs): Cambridge GIST study group experience. Ann Oncol 2005;16(Suppl. 2):311.

Bulusu V, Fawcett S, Cook N, Hatcher H, Moyle P, Carroll N, et al. Size does not matter! Patterns of response and progression in patients (PTS) with metastatic gastrointestinal stromal tumours (GISTS) on imatinib mesylate (IM). Ann Oncol 2006;17(Suppl. 6):100.

Casali P, Fumagalli E, Bello A, George S. Safety and tolerability of sunitinib (SU) initiated 24 h after the last dose of imatinib (IM) in advanced GIST. J Clin Oncol 2008;26(Suppl. 5):Abstract 10557.

Chen C-W. Surgical management and clinical outcome of gastro-intestinal stromal tumor of the colon and rectum. Z Gastroenterol 2008;46:760–5.

Chen MY, Bechtold RE, Savage PD. Cystic changes in hepatic metastases from gastrointestinal stromal tumors (GISTs) treated with Gleevec (imatinib mesylate). Am J Roentgenol 2002;179:1059–62.

Chen TW, Liu HD, Shyu RY, Yu JC, Shih ML, Chang TM, et al. Giant malignant gastrointestinal stromal tumors: recurrence and effects of treatment with STI-571. World J Gastroenterol 2005;11:260–3.

Cipolla C, Fulfaro F, Sandonato L, Fricano S, Pantuso G, Grassi N, et al. Clinical presentation and treatment of gastrointestinal stromal tumors. Tumori 2006;92:279–84.

De Giorgi U, Aliberti C, Benea G, Conti M, Marangolo M. Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 2005;11:6171–6.

Gibbons J, Egorin MJ, Ramanathan RK, Fu PF, Mulkerin DL, Shibata S, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 2008;26:570–6.

Gronchi A, Fiore M, Miselli F, Lagonigro MS, Coco P, Messina A, et al. Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg 2007;245:341–6.

Harney J, Wong WI, Short S. A preliminary evaluation of the potential role of FDG-PET to assess response to Glivec (TM) in gastrointestinal stromal tumours (GISTs). Br J Cancer 2003;88(Suppl. 1):S41.

Hasegawa J, Kanda T, Hirota S, Fukuda M, Nishitani A, Takahashi T, et al. Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy. Int J Clin Oncol 2007;12:212–17.

Hassan I, You YN, Dozois EJ, Shayyan R, Smyrk TC, Okuno SH, et al. Clinical, pathologic, and immunohistochemical characteristics of gastrointestinal stromal tumors of the colon and rectum: implications for surgical management and adjuvant therapies. Dis Colon Rectum 2006;49:609–15.

Hsiao HH, Liu YC, Tsai HJ, Chen LT, Lee CP, Chuan CH, et al. Imatinib mesylate therapy in advanced gastrointestinal stromal tumors: experience from a single institute. Kaohsiung J Med Sci 2006;22:599–603.

Kasper B, Kallinowski B, Herrmann T, Lehnert T, Mechtersheimer G, Geer T, et al. Treatment of gastrointestinal stromal tumor with imatinib mesylate: a retrospective single-center experience in Heidelberg. Dig Dis 2006;24:207–11.

Lasota J, vel Dobosz AJ, Wasag B, Wozniak A, Kraszewska E, Michej W, et al. Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. Lab Invest 2007;87:1029–41.

Maehara N, Chijiiwa K, Eto T, Funagayama M, Uchiyama S, Nakashima S, et al. Surgical treatment for gastric GIST with special reference to liver metastases. Hepatogastroenterology 2008;55:512–16.

Mearadji A, den Bakker MA, van Geel AN, Eggermont AM, Sleijfer S, Verweij J, et al. Decrease of CD117 expression as possible prognostic marker for recurrence in the resected specimen after imatinib treatment in patients with initially unresectable gastrointestinal stromal tumors: a clinicopathological analysis. Anticancer Drugs 2008;19:607–12.

Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 2008;14:4550–5.

Neagu S, Costea R, Sajin M, Ardelean C, Zarnescu NO. Gastric stromal tumors: histopathological, clinical and therapeutical aspects. Proceedings of the 8th International Gastric Cancer Congress, Krakow, Poland, 10–13 June 2009, pp. 85–7.

Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci 2008;99:799–804.

Nishida T, Takahashi T, Nishitani A, Doi T, Shirao K, Komatsu Y, et al. Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol 2009;14:143–9.

Ohnishi K, Sakai F, Kudoh S, Ohno R. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia 2006;20:1162–4.

Petricevic B, Vrbanec D, Belev B, Plestina S, Herceg D, Dedic-Plavetic N. Imatinib mesylate in treatment of advanced gastrointestinal stromal tumours. Ann Oncol 2005;16(Suppl. 2):313.

Prakash S, Sarran L, Socci N, Dematteo RP, Eisenstat J, Greco AM, et al. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 2005;27:179–87.

Raut C, Van den Abbeele A, Ramaiya N, Morgan J, George S, Quigley M, et al. PET imaging demonstrates two patterns of response in GIST patients benefiting from long-term sunitinib therapy. Ann Oncol 2006;17(Suppl. 6):103.

Richter KK, Schmid C, Thompson-Fawcett M, Settmacher U, Altendorf-Hofmann A. Long-term follow-up in 54 surgically treated patients with gastrointestinal stromal tumours. Langenbecks Arch Surg 2008;393:949–55.

Rutkowski P, Nyckowski P, Grzesiakowska U, Nowecki ZI, Nasierowska-Guttmejer A, Pienkowski A, et al. The clinical characteristics and the role of surgery and imatinib treatment in patients with liver metastases from c-Kit positive gastrointestinal stromal tumors (GIST). Neoplasma 2003;50:438–42.

Salazar LIF, Gago TA, Rubiales AS, Jimenez BV, de la Fuente RA, Hernandez JMG. Gastrointestinal stromal tumors (GIST): clinical aspects. Rev Esp Enferm Dig 2007;99:19–24.

Scaife CL, Hunt KK, Patel SR, Benjamin RS, Burgess MA, Chen LL, et al. Is there a role for surgery in patients with ‘unresectable’ cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate? Am J Surg 2003;186:665–9.

Schindler CG, Armbrust T, Gunawan B, Langer C, Fuzesi L, Ramadori G. Gastrointestinal stromal tumor (GIST): single center experience of prolonged treatment with imatinib. Z Gastroenterol 2005;43:267–73.

Sym SJ, Ryu MH, Lee JL, Chang HM, Kim TW, Kim HC, et al. Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol 2008;98:27–33.

Tham C-K. Gastrointestinal stromal tumour in the elderly. Crit Rev Oncol Hematol 2009;70:256–61.

Tsukuda K, Hirai R, Miyake T, Takagi S, Ikeda E, Kunitomo T, et al. The outcome of gastrointestinal stromal tumors (GISTs) after a surgical resection in our institute. Surg Today 2007;37:953–7.

Van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato dP, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3.

Wang CM, Fu H, Zhao GF, Zhou XY, Du CY, Dong RZ, et al. Secondary resistance to imatinib in patients with gastrointestinal stromal tumors through an acquired KIT exon 17 mutation. Mol Med Report 2009;2:455–60.

Warakaulle DR, Gleeson F. MDCT appearance of gastrointestinal stromal tumors after therapy with imatinib mesylate. Am J Roentgenol 2006;186:510–15.

Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, et al. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 2008;99:448–54.

Wong DW, Lupton SC, Bhatt L, Gross L, Taniere P, Peake DR, et al. Use of imatinib mesylate in gastrointestinal stromal tumours: Pan-Birmingham Cancer Network experience. Clin Oncol 2008;20:517–22.

Wu A-W. Gastrointestinal stromal tumors of the anorectum – a special entity: GISTs of the anorectum. Chinese J Cancer Res 2006;18:38–44.

Zhu J, Wang Y, Hou M, Li HY, Zhang J. Imatinib mesylate treatment for advanced gastrointestinal stromal tumor: a pilot study focusing on patients experiencing sole liver metastasis after a prior radical resection. Oncology 2007;73:324–7.

400 mg/day imatinib dose only (n = 13)

Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 2007;25:1107–13.

Bumming P, Andersson J, Meis-Kindblom JM, Klingenstierna H, Engstrom K, Stierner U, et al. Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: a centre-based study of 17 patients. Br J Cancer 2003;89:460–4.

Choi H, Charnsangavej C, de Castro FS, Tamm EP, Benjamin RS, Johnson MM, et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET finding. Am J Roentgenol 2004;183:1619–28.

Delbaldo C, Chatelut E, Re M, Deroussent A, Jambu A, Mackrodt A, et al. Inflammatory response affects the pharmacokinetics (PK) and pharmacodynamics (PD) of imatinib and CGP 74588 in patients with advanced gastrointestinal sarcoma (GIST). J Clin Oncol 2004;22:2070.

Dematteo RP, Antonescu CR, Chadaram V, You YN, McCall L, Maki R, et al. Adjuvant imatinib mesylate in patients with primary high risk gastrointestinal stromal tumor (GIST) following complete resection: safety results from the US Intergroup Phase II trial ACOSOG Z9000. J Clin Oncol 2005;23:S818.

Kim TW, Ryu MH, Lee H, Sym SJ, Lee JL, Chang HM, et al. Kinase mutations and efficacy of imatinib in Korean patients with advanced gastrointestinal stromal tumors. Oncologist 2009;14:540–7.

Le Cesne A, Rav-Coquard I, Bul B, Duffaud F, Deligny N, Cupissol D, et al. Interruption of imatinib (IM) in responding patients after one year treatment does not influence overall survival of patients with advanced GIST: updated results of the French Sarcoma Group randomized phase III BFR14 trial. Eur J Cancer 2005;3:S202.

Le Cesne A, Perol D, Ray-Coquard I, Bui B, Duffaud F, Rios M, et al. Interruption of imatinib (IM) in GIST patients with advanced disease: updated results of the prospective French Sarcoma Group randomized phase III trial on survival and quality of life. J Clin Oncol 2005;23:823S.

Steinert DM, Oyarzo M, Wang X, Choi H, Thall PF, Medeiros LJ, et al. Expression of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate. Cancer 2006;106:1617–23.

Van den Abbeele AD, Badawi RD, Tetrault RJ, Cliche JP, Manola J, Spangler T, et al. FDG-PET as a surrogate marker for response to Gleevec (TM) (imatinib mesylate) in patients with advanced gastrointestinal stromal tumors (GIST). J Nucl Med 2003;44:77.

Widmer N, Decosterd LA, Leyvraz S, Duchosal MA, Rosselet A, Debiec-Rychter M, et al. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br J Cancer 2008;98:1633–40.

Yeh CN, Chen TW, Liu FY, Jan YY, Chen MF. Genetic changes in advanced gastrointestinal stromal tumor (GIST) patients during imatinib mesylate treatment. Langenbecks Arch Surg 2006;391:615–21.

Yeh CN, Chen TW, Wu TJ, Hsueh S, Jan YY. Treatment of patients with advanced gastrointestinal stromal tumor of small bowel: implications of imatinib mesylate. World J Gastroenterol 2006;12:3760–5.

No/insufficient data for escalated dose patients (n = 65)

Aliberti S, Grignani G, Allione P, Vormola R, Bucci AS, Porrino G, et al. Erythrocyte macrocytosis is a rather common, apparently uneventful yet unexplained finding in GIST imatinib (I) chronic therapy. J Clin Oncol 2005;23:S827.

Allione P, Grignani G, Aliberti S, Scalabrini DR, Schianca FC, Capaldi A, et al. Increase of creatine kinase value (CK) correlates with muscoloskeletal complaints (MSC) in GIST patients during imatinib therapy. J Clin Oncol 2006;24:9509.

An JY, Choi MG, Noh JH, Sohn TS, Kang WK, Park CK, et al. Gastric GIST: a single institutional retrospective experience with surgical treatment for primary disease. Eur J Surg Oncol 2007;33:1030–5.

Barman B, Gupta P, Sen AN, Deb S, Sarkar S, Mukhopadhyay S, et al. Imatinib mesylate as first-line therapy in patients with gastro intestinal stomach tumour (GIST): an experience of 24 cases from India. Ann Oncol 2005;16(Suppl. 2):311.

Benjamin RS, Rankin C, Fletcher C, Blanke C, von Mehren M, Maki R, et al. Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: intergroup S0033 early results abstract. 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, 31 May to 3 June 2003, abstract no. 3271.

Bhattacharjee C, Mukhopadhyay S, Dey S, Basak J, Dutta S, Mukhopadhyay A. Tolerance of imatinib mesylate inpatients with gastro intestinal stromal tumour (GIST): an Indian experience. Ann Oncol 2008;19(Suppl. 5):167.

Blanke CD, von Mehren M, Joensuu H, Roberts PJ, Eisenberg B, Heinrich M, et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTS) expressing C-KIT (CD117). 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, 12–15 May 2001, abstract no. 1.

Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg BL, Fletcher J, et al. Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate. J Clin Oncol 2006;24:9528.

Casali PG, Verwell J, Zalcberg J, LeCesne A, Reichardt P, Ray Coquard I, et al. Imatinib (Glivec) 400 vs 800 mg daily in patients with gastrointestinal stromal tumours (GIST): a randomized phase III trial from the EORTC Soft Tissue & Bone Sarcoma Group, the Italian Sarcoma Group (ISG) and the Australasian Gastro-Intestinal Trials Group (AGITG). A toxicity report abstract. 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, 18–21 May 2002, abstract no. 413.

Casali PG, Verweij J, Kotasek D, LeCesne A, Reichardt P, Blay JY, et al. Imatinib mesylate in advanced gastrointestinal stromal tumors (GIST): survival analysis of the intergroup EORTC/ISG/AGITG randomized trial in 946 patients. Eur J Cancer 2005;3:S201–2.

Choi D, Yoo EY, Kim KM, Sohn TS, Lee WJ, Lee JY, et al. Residual and recurrent gastrointestinal stromal tumors with KIT mutations: findings at first follow-up CT after imatinib treatment. Am J Roentgenol 2009;193:W100–5.

Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689–95.

DeMatteo R. Adjuvant imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gastrointestinal stromal tumor. J Clin Oncol 2007;25(Suppl. 18):Abstract 10079.

Demetri GD, Rankin C, Fletcher C, Benjamin RS, Blanke C, Von Mehren N, et al. Phase III dose-randomized study of imatinib mesylate (Gleevec, STI571) for GIST: intergroup S0033 early results abstract. 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, 18–21 May 2002, abstract no. 1651.

Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 2009;27:3141–7.

Dincer S, Akboru H, Teke F, Eren B, Askaroglu B, Demir C, et al. Evaluation of gastrointestinal stromal tumor patients and imatinib therapy. Ann Oncol 2008;19(Suppl. 8):270–1.

Doi T, Nishida T, Hirota S, Sugiyama T, Yamao K, Koseki M, et al. Phase II clinical study of STI571 in Japanese (Jpn) patients (pts) with malignant gastrointestinal stromal tumors (GIST): results of the B 1201 study abstract. 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 5–8 June 2004, abstract no. 4078.

Duffaud F, Le Cesne A. Imatinib in the treatment of solid tumours. Target Oncol 2009;4:45–56.

Goerres GW, Stupp R, Barghouth G, Hany TF, Pestalozzi B, Dizendorf E, et al. The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate. Eur J Nucl Med Mol Imaging 2005;32:153–62.

Hartmann JT, Heidel F, Stoehlmacher J, Duex M, Izbicki JR, Elsaid A, et al. Pattern of progression and its impact on outcome in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: a retrospective multicenter long-term follow-up study. J Clin Oncol 2006;24:9541.

Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342–9.

Heinrich MC, Shoemaker JS, Corless CL, Hollis D, Demetri GD, Bertagnolli MM, et al. Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+). J Clin Oncol 2005;23(Suppl. 16):7.

Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008;26:5360–7.

Hohenberger P. Neoadjuvant imatinib and organ preservation in locally advanced gastrointestinal stromal tumors (GIST). J Clin Oncol 2009;27(Suppl. 15):Abstract 10550.

Joensuu H, De Braud F, Coco P, De Pas T, Spreafico C, Bono P, et al. A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs) resistant to imatinib mesylate. J Clin Oncol 2006;24:9531.

Joensuu H, Demetri GD, Heinrich MC, Eisenberg BL, Fletcher JA, Corless CL, et al. Up to 6 years’ follow-up of patients receiving imatinib mesylate (Glivec) to treat unresectable or metastatic gastrointestinal stromal tumors (GISTs). Eur J Cancer 2007;5:S7506.

Judson IR, Verweij J, Van Oosterom A, Blay JY, Rodenhuis S, van der Graaf W, et al. Imatinib (Gleevec) an active agent for gastrointestinal stromal tumours (GIST), but not for other soft tissue sarcoma (STS) subtypes not characterized for KIT and PGDF-R expression: results of EORTC phase II studies. Proc Am Soc Clin Oncol 2002;21:Abstract 1609.

Kang B. A phase II study of imatinib mesylate as adjuvant treatment for curatively resected high-risk localized GIST. J Clin Oncol 2009;27(Suppl.):Abstract e21515.

Le Cesne A. Continuous versus interruption of imatinib in responding patients. J Clin Oncol 2007;25(Suppl. 18):Abstract 10005.

Le Cesne A, Van Glabbeke M, Verweij J, Casali P, Zalcberg J, Reichardt P, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? J Clin Oncol 2006;24:9510.

Le Cesne A, Van Glabbeke M, Verweij J, Casali PG, Findlay M, Reichardt P, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol 2009;27:3969–74.

Lee JL, Ryu MH, Chang HM, Kim TW, Kang HJ, Sohn HJ, et al. Clinical outcome in gastrointestinal stromal tumor patients who interrupted imatinib after achieving stable disease or better response. Jpn J Clin Oncol 2006;36:704–11.

Li J. Adjuvant therapy with imatinib in gastrointestinal stromal tumor (GIST) patients with intermediate or high risk. J Clin Oncol 2009;27(15S):Abstract 10556.

Menard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res 2009;69:3563–9.

Nishida T. Preliminary results of the phase II clinical trial of imatinib mesylate for advanced gastrointestinal stromal tumors in Japan. Gann Mono Cancer Res 2004;53:151–7.

Nishida T, Shirao K, Sawaki A, Koseki M, Okamura T, Ohtsu A, et al. Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202). Int J Clin Oncol 2008;13:244–51.

Perol D. Does interruption of imatinib in responding GIST patients after one year of treatment influence the secondary resistance to IM after its reintroduction? J Clin Oncol 2008;26(Suppl. 5):Abstract 10556.

Phongkitkarun S, Phaisanphrukkun C, Jatchavala J, Sirachainan E. Assessment of gastrointestinal stromal tumors with computed tomography following treatment with imatinib mesylate. World J Gastroenterol 2008;14:892–8.

Rios M. Interruption of imatinib in GIST patients with advanced disease after one year of treatment. J Clin Oncol 2007;25(Suppl. 18):Abstract 10016.

Romeo S, Debiec-Rychter M, Van Glabbeke M, Van Paassen H, Comite P, Van Eijk R, et al. Cell cycle/apoptosis molecule expression correlates with imatinib response in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res 2009;15:4191–8.

Ruka W. The outcomes of patients with metastatic/inoperable gastrointestinal stromal tumors (GIST) treated with imatinib: an interim multicenter analysis of Polish Clinical GIST Registry. Nowotwory 2005;55:195–9.

Rutkowski P, Debiec-Rychter M, Nowecki ZI, Wozniak A, Michej W, Limon J, et al. Different factors are responsible for predicting relapses after primary tumors resection and for imatinib treatment outcomes in gastrointestinal stromal tumors. Med Sci Monitor 2007;13:CR515–22.

Rutkowski P, Nowecki ZI, Debiec-Rychter M, Grzesiakowska U, Michej W, Wozniak A, et al. Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+) gastrointestinal stromal tumors (GISTs). J Cancer Res Clin Oncol 2007;133:589–97.

Rutkowski P, Nowecki ZI, Grzesiakowska U, Michej W, Debiec-Rychter M, Wozniak A, et al. Long-term effects of imatinib therapy and impact of surgery on patients (pts) with CD117(+) gastrointestinal stromal tumours (GIST) without early progression on imatinib. Society of Surgical Oncology 60th Annual Cancer Symposium March 2007, Washington DC, USA, poster P280.

Ryu M, Lee J, Chang H, Kim T, Kang H, Sohn H, et al. Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Eur J Cancer 2005;3:S23.

Ryu MH, Lee JL, Chang HM, Kim TW, Kang HJ, Sohn HJ, et al. Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Jpn J Clin Oncol 2006;36:17–24.

Ryu MH, Kang WK, Bang YJ, Lee KH, Shin DB, Ryoo BY, et al. A prospective, multicenter, phase 2 study of imatinib mesylate in Korean patients with metastatic or unresectable gastrointestinal stromal tumor. Oncology 2009;76:326–32.

Sawaki A. Recurrence after imatinib treatment for patients with gastrointestinal stromal tumor. J Gastroenterol Hepatol 2006;21(Suppl. 6):A499.

Sciot R, Debiec-Rychter M, Daugaard S, Fisher C, Collin F, Van Glabbeke M, et al. Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GISTs): an analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate. Eur J Cancer 2008;44:1855–60.

Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 2003;39:2012–20.

Tamas KR, Papai Z, Vegh EA, Petranyi AE, Szucs Z, Rohanszky M, et al. One institutional experience with imatinib mesylate in the treatment of gastrointestinal stromal tumors. Ann Oncol 2006;17(Suppl. 9):164.

van Erp N, Gelderblom H, Van Glabbeke M, Van Oosterom A, Verweij J, Guchelaar HJ, et al. Effect of cigarette smoking on imatinib in patients in the soft tissue and bone sarcoma group of the EORTC. Clin Cancer Res 2008;14:8308–13.

Van Glabbeke MM, Verweij J, Casali PG, Zalcberg J, Le Cesne A, Reichard P, et al. Prognostic factors of toxicity and efficacy in patients with gastro-intestinal stromal tumors (GIST) treated with imatinib: a study of the EORTC-STBSG, ISG and AGITG. Proc Am Soc Clin Oncol 2003;818:Abstract 3288.

Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I, et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 2005;23:5795–804.

Van Glabbeke M, Verweij J, Casali PG, Simes J, Le Cesne A, Reichardt P, et al. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer 2006;42:2277–85.

Van Glabbeke M, Owzar K, Rankin C, Simes J, Crowley J, GIST Meta-analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumours (GIST): a meta-analysis based on 1640 patients. J Clin Oncol 2007;25(Suppl. 18):Abstract 10004.

Van Oosterom AT, Judson IR, Verweij J, Stroobants S, Dumez H, Donato dP, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38(Suppl. 5):S83–7.

Verweij J, Casali PG, Zalcberg J, Le Cesne A, Reichard P, Blay J, et al. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastro-intestinal stromal tumors (GIST): interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG. Proc Am Soc Clin Oncol 2003;22:Abstract 3272.

Verweij J, Van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der GW, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39:2006–11.

Verweij J, Casali PG, Kotasek D, Le Cesne A, Reichard P, Judson IR, et al. Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005. Eur J Cancer 2007;43:974–8.

Villalobos R. Clinical response to imatinib mesylate in recurrent and metastaic gastrointestinal stromal tumors. J Clin Oncol 2007;25(Suppl. 18):Abstract 20528.

von Mehren M. Imatinib response linked to variations in drug exposure. Oncology Report 2008;fall:31.

Yeh CN, Chen TW, Lee HL, Liu YY, Chao TC, Hwang TL, et al. Kinase mutations and imatinib mesylate response for 64 Taiwanese with advanced GIST: preliminary experience from Chang Gung Memorial Hospital. Ann Surg Oncol 2007;14:1123–8.

Yildiz I, Mandel NM, Demir G, Ozguroglu M, Toptas T, Buyukunal E, et al. Imatinib mesylate response in gastrointestinal stromal tumors: experience of Cerrahpasa Medical Faculty. Ann Oncol 2006;17(Suppl. 9):164.

Zekri JM, Robinson MH. Relative hypocalcaemia and muscle cramps in patients receiving imatinib for gastrointestinal stromal tumour. Sarcoma 2006;2006:Article ID 48948.

Imatinib dose not reported (n = 84)

Al Batran SE, Hartmann JT, Heidel F, Stoehlmacher J, Wardelmann E, Dechow C, et al. Focal progression in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: a three-center-based study of 38 patients. Gastric Cancer 2007;10:145–52.

Artinyan A, Kim J, Soriano P, Ellenhorn J. Survival from metastatic gastrointestinal stromal tumors in the era of imatinib. Ann Surg Oncol 2008;15(Suppl. 2):92.

Bachet J, Hostein I, Le Cesne A, Beauchet A, Brahimi S, Tabone-Eglinger S, et al. GIST with deletion of TYR568 and TYR570 of kit have similar prognosis and response to imatinib as those with DELWK557–558, but are mainly extra-gastric. Ann Oncol 2008;19(Suppl. 6):9.

Bachet JB, Hostein I, Le Cesne A, Brahimi S, Beauchet A, Tabone-Eglinger S, et al. Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer 2009;101:7–11.

Bao X, Kamo N, Hao H, Sakurama K, Noma K, Shirakawa Y, et al. The upregulation of FAK contributes to tumor progression and a resistance to imatinib in gastrointestinal stromal tumor. Proceedings of the American Association for Cancer Research Annual Meeting 2009, p. 50.

Basu S, Balaji S, Bennett DH, Davies N. Gastrointestinal stromal tumors (GIST) and laparoscopic resection. Surg Endosc 2007;21:1685–9.

Bearzi I, Mandolesi A, Arduini F, Costagliola A, Ranaldi R. Gastrointestinal stromal tumor. A study of 158 cases: clinicopathological features and prognostic factors. Anal Quant Cytol Histol 2006;28:137–47.

Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, et al. Response of gastrointestinal stromal tumors (GISTs) to imatinib by Choi criteria and response evaluation criteria in solid tumors (RECIST) as surrogates for survival and time to progression. J Clin Oncol 2006;24:9506.

Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007;25:1760–4.

Blackstein M, Huang X, Demetri G, Casali P, Garrett C, Schoffski P, et al. Investigation of soluble KIT as a potential surrogate marker for TTP in sunitinib-treated patients with GIST. Ann Oncol 2007;18(Suppl. B):VII16.

Boulos BM, Jajeh A, Nawaz U, Osafo D, Tamkus D, Ogundipe O, et al. Retrospective analysis of the use of imatinib mesylate in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). FASEB J 2007;21:A1189.

Bui BN, Le Cesne A, Ray-Coquard I, Duffaud F, Rios M, Adenis A, et al. Do patients with initially resected metastatic GIST benefit from ‘adjuvant’ imatinib (IM) treatment? Results of the prospective BFR14 French Sarcoma Group randomized phase III trial. J Clin Oncol 2006;24:9501.

Casali P, Garrett C, Blackstein M, Shah M, Verweij J, McArthur G, et al. A phase III trial of sunitinib in GIST patients following failure of imatinib mesylate: updated trial results. Ann Oncol 2006;17(Suppl. 6):21–2.

Casali PG, Fumagalli E, Messina A, Spreafico C, Comandini D, Camadone A, et al. Tumor response to imatinib mesylate in advanced GIST. J Clin Oncol 2004;22:9028.

Casali PG, Garrett CR, Blackstein ME, Shah M, Verweij J, McArthur G, et al. Updated results from a phase III trial of sunitinib in GIST patients (pts) for whom imatinib (IM) therapy has failed due to resistance or intolerance. J Clin Oncol 2006;24:9513.

Cassier P, Fayette J, Ray-Coquard I, Bui B, Duffaud F, Adonis A, et al. Outcome of patients with locally advanced GIST receiving imatinib mesylate in a prospective trial. Ann Oncol 2007;18(Suppl. 7):VII105–6.

Chevreau C. Outcome of patients with advanced GIST achieving a complete remission. J Clin Oncol 2009;27(Suppl. 15):Abstract 10549.

Choi H, Tamm EP, Macapinlac HA, Faria S, Podoloff DA, Broemeling LD, et al. The role of CT density measurement to monitor the gastrointestinal stromal tumors after treatment with STI-571: a quantitative analysis. Clin Cancer Res 2001;7:233.

Choi H, Faria SC, Benjamin RS, Podoloff DA, Macapinlac HA, Charnsangavej C. Monitoring treatment effects of STI-571 on gastrointestinal stromal tumors (GIST) with CT and PET: a quantitative analysis. Radiology 2002;225(Suppl. S):583.

Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–9.

Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007;370:2011–19.

Cioffi A. Long term progression-free survval correlates with KIT/PDGFR. J Clin Oncol 2007;25(Suppl. 18):Abstract 10053.

Cioffi A. Outcomes for patients with advanced GIST. J Clin Oncol 2008;26(Suppl. 5):Abstract 10550.

Davis D, Heymach J, McConkey D, Desai J, George S, Jackson J, et al. Receptor tyrosine kinase activity and apoptosis in gastrointestinal stromal tumours: a pharmacodynamic analysis of response to sunitinib malate (SU11248) therapy. Clin Cancer Res 2005;11:S9027.

De Giorgi U, Aliberti C, Benea G, Kopf B, Marangolo M. Effect of angio-echography with a second-generation contrast agent to assess tumor response to imatinib treatment in patients with advanced gastrointestinal stromal tumor (GIST): comparison with computerized tomography (CT). J Clin Oncol 2004;22:4216.

Demetri G, Huang X, Garrett C, Schoffski P, Blackstein M, Shah MH, et al. Novel statistical analysis of long-term survival to account for crossover in a phase III trial of sunitinib (SU) vs placebo (PL) in advanced GIST after imatinib failure. J Clin Oncol 2009;26(Suppl. 5):Abstract 10524.

Demetri GD, Desai J, Fletcher JA, Morgan JA, Fletcher CDM, Kazanovicz A, et al. SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol 2004;22:3001.

Demetri GD, Van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–38.

Demetri GD, Heinrich MC, Fletcher JA, Fletcher CD, Van den Abbeele AD, Corless CL, et al. Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. Clin Cancer Res 2009;15:5902–9.

Deprimo SE, Huang X, Blackstein ME, Garrett CR, Harmon CS, Schoffski P, et al. Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res 2009;15:5869–77.

Desai J, Dileo P, Morgan JA, Larsen PR, Chen MH, George S, et al. Hypothyroidism may accompany SU11248 therapy in a subset of patients (pts) with metastatic (met) gastrointestinal stromal tumors (GIST) and is manageable with replacement therapy. J Clin Oncol 2005;23:S201.

Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145:660–4.

Dileo P, Morgan JA, Garrett CR, Schutte HJ, Hurwitz H, Rosen LS, et al. Updated results from a ‘treatment-use’ trial of sunitinib in advanced gastrointestinal stromal tumor (GIST). Ann Oncol 2006;17(Suppl. 9):162–3.

Doi V, Shirao K, Yamada Y, Muro K, Fuse N, Euda E, et al. Sunitinib in Japanese patients with GIST after prior treatment with imatinib mesylate: a phase I/II dose-escalation study. Ann Oncol 2006;17(Suppl. 6):101.

Efthirniou E, Mudan S, Hayes A, Judson I, Thomas M. Pre-operative imatinib for recurrent, metastatic and locally advanced gastrointestinal tumours (GIST). Ann Oncol 2008;19(Suppl. 6):72.

Ferreira TC, Vieira MR, Salazar M, Nobre-Leitao C. Importance of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scan in the evaluation of patients (pts) with gastrointestinal stromal tumour (GIST) under imatinib mesylate (IMT): one year of experience. Eur J Nucl Med Mol Imaging 2004;31(Suppl. 2):335.

Fiore M, Palassini E, Fumagalli E, Pilotti S, Tamborini E, Stacchiotti S, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol 2009;35:739–45.

Garrett C, Huang X, Casali P, Schoffski P, Blackstein M, Shah M, et al. Long-term survival in a phase III trial of sunitinib in imatinib-resistant/intolerant gastrointestinal stromal tumor with novel statistical analysis to account for crossover. Ann Oncol 2008;19(Suppl. 6):12.

Gomez D, Al Mukthar A, Menon KV, Toogood GJ, Lodge JP, Prasad KR. Aggressive surgical resection for the management of hepatic metastases from gastrointestinal stromal tumours: a single centre experience. HPB 2007;9:64–70.

Gong JS, Zuo M, Yang P, Zang D, Zhang Y, Xia L, et al. Value of CT in the diagnosis and follow-up of gastrointestinal stromal tumors. Clin Imaging 2008;32:172–7.

Heinrich MC. Does tumor mutational status correlate with clinical response to imatinib? Commentary. Nature Clin Pract Oncol 2006;3:600–1.

Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008;26:5352–9.

Hohenberger P, Langer C, Pistorius S, Iesalnieks I, Wardelmann E, Reichardt P. Indication and results of surgery following imatinib treatment of locally advanced or metastatic GI stromal tumors (GIST). J Clin Oncol 2006;24:9500.

Holdsworth CH, Manola J, Badawi RD, Israel DA, Blanke C, von Mehren M, et al. Use of computerized tomography (CT) as an early prognostic indicator of response to imatinib mesylate (IM) in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol 2004;22:3011.

Hong X, Choi H, Loyer EM, Benjamin RS, Trent JC, Charnsangavej C. Gastrointestinal stromal tumor: role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. Radiographics 2006;26:481–95.

Janicek MJ, Potter A, Merriam P, Demetri GD. Does pattern of metastases and early measurable changes after treatment predict therapy effect in gastrointestinal stromal tumor (GIST) on STI571 (imatinib)? Radiology 2002;225(Suppl. S):583.

Jin J, Robinson A, Willis J, Hardacre J, Kim J. Does imatinib mesylate (IM) affect longterm outcome in patients with gastrointestinal stromal tumors (GISTs)? J Am Coll Surg 2007;205:S14.

Judson IR, Casali PG, Garrett CR, Blackstein ME, Shah M, Verweij J, et al. Updated results from a phase III trial of sunitinib in advanced gastrointestinal stromal tumor (GIST). Ann Oncol 2006;17(Suppl. 9):162.

Kaneta T, Takahashi S, Fukuda H, Arisaka Y, Oriuchi N, Hayashi T, et al. Clinical significance of performing F-18-FDG PET on patients with gastrointestinal stromal tumors: a summary of a Japanese multicenter study. Ann Nucl Med 2009;23:459–64.

Kim TW, Ryu MH, Lee H, Lee SS, Sym SJ, Kim MK, et al. No relationship between C-kit mutation and response to imatinib in Korean patients with metastatic gastrointestinal stromal tumor. Ann Oncol 2006;17(Suppl. 9):162.

Kleinbaum EP, Lazar AJ, Tamborini E, McAuliffe JC, Sylvestre PB, Sunnenberg TD, et al. Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor. Int J Cancer 2008;122:711–18.

Kuhlmann KFD, Kerst JM, Cats A, van Coevorden F. Is there a role for post-imatinib surgery in advanced gastrointestinal stromal tumours? Eur J Gastroenterol Hepatol 2009;21:A3.

Lamuraglia M, Le Cesne A, Chami L, Bonvalot S, Terrier P, Tursz T, et al. Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is a useful radiological assessment to early predict the outcome of patients with gastrointestinal stromal tumors (GIST) treated with imatinib (IM). J Clin Oncol 2006;24:9539.

Lassau N, Lamuraglia M, Leclere J, Bonvalot S, Vanel D, Robert C, et al. Doppler-ultrasonography with perfusion software and contrast medium injection as an early evaluation tool of gastro intestinal stromal tumor (GIST) treated by imatinib: results of a prospective study. J Clin Oncol 2004;22:9048.

Lassau N, Lamuraglia M, Chami L, Le Cesne A, Roche A, Leclere L, et al. Interest of Doppler-ultrasonography with perfusion software and contrast injection to early evaluation and detection of secondary resistence of gastrointestinal stromal tumors treated with imatinib. Eur J Cancer 2005;3:S320.

Lee J, Ryu M, Chang H, Kim T, Kang H, Sohn H, et al. Clinical outcome in gastrointestinal stromal tumor patients who interrupted imatinib after achieving stable disease or better response. Eur J Cancer 2005;3(Suppl.):64.

Lichinitser M. Molecular biomarkers and imatinib efficacy in metastatic gastrointestinal stromal tumors. J Clin Oncol 2008;26(Suppl. 5):Abstract 21500.

Maki R, Fletcher JA, Heinrich M, Morgan JA, George S, Desai J, et al. Results from a continuation trial of SU11248 in patients with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol 2005;23(Suppl.):Abstract 9011.

Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metabol 2007;92:3531–4.

Morgan JA, Demetri GD, Fletcher JA, George S, Desai J, Maki RG, et al. Patients with imatinib mesylate-resistant GIST exhibit durable responses to sunitinib malate (SU11248). Eur J Cancer 2005;3:S421.

Morgan JA, Garrett CR, Schutte HJ, Hurwitz H, Rosen LS, Ruka W, et al. Sunitinib for patients (pts) with advanced imatinib (IM)-refractory GIST: early results from a ‘treatment-use’ trial. J Clin Oncol 2006;24:9540.

Nishida T, Doi T, Komatsu Y, Ueda E, Baum C, Shirao K. Sunitinib treatment of GIST in Japanese patients after failure of prior imatinib treatment: a phase II trial. Ann Oncol 2007;18(Suppl. 7):VII110.

Park SS, Ryu JS, Oh SY, Kim WB, Lee JH, Chae YS, et al. Surgical outcomes and immunohistochemical features for gastrointestinal stromal tumors (GISTS) of the stomach: with special reference to prognostic factors. Hepatogastroenterology 2007;54:1454–7.

Pawlik TM, Vauthey JN, Abdalla EK, Pollock RE, Ellis LM, Curley SA. Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg 2006;141:537–43.

Perez EA, Livingstone AS, Franceschi D, Rocha-Lima C, Lee DJ, Hodgson N, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg 2006;202:623–9.

Prior JO, Montemurro M, Orcurto MV, Michielin O, Luthi F, Benhattar J, et al. Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol 2009;27:439–45.

Raut C. Clinical experience with periopertaive sunitinib and extensive resection of imatinib resistant metastatic GIST. Ann Oncol 2007;18(Suppl. 7):123.

Raut C. Perioperative sunitinib dosing around extensive resections of imatinib-resistant metastatic gastrointestinal stromal tumors. J Clin Oncol 2007;25(Suppl. 18):Abstract 10044.

Reichardt P, Kang Y, Ruka W, Seddon B, Baum C, Demetri G. Subpopulation analysis in a world wide treatment-use trial of sunitinib (SU) in GIST patients with resistance or intolerance to prior imatinib (IM) therapy. J Clin Oncol 2007;25(Suppl. 18):Abstract 10022.

Rutkowski P, Nowecki Z, Nyckowski P, Dziewirski W, Nasierowska-Guttmejer A, Grzesiakowska U, et al. Surgical treatment of patients (pts) with gastrointestinal stromal tumors (GIST) after imatinib mesylate (IM) therapy. J Clin Oncol 2005;23:S825.

Rutkowski P, Nowecki ZI, Michej W, Debiec-Rychter M, Limon J, Siedlecki JA, et al. The criteria of aggressiveness and other prognostic factors for predicting relapses of primary tumors and imatinib (IM) treatment outcomes in advanced KIT immunopositive gastrointestinal stromal tumors (GIST): a report of the Polish Clinical GIST Registry (PCGR). J Clin Oncol 2006;24(Suppl. 18):Abstract 9544.

Ryu MH, Lee JL, Chang HM, Kim TW, Kim HC, Yook JH, et al. Surgical resection after imatinib treatment in patients with metastatic or unresectable gastrointestinal stromal tumors. Ann Oncol 2006;17(Suppl. 9):164.

Schoffski P, Huang X, Casali PG, Garrett CR, Blackstein ME, Shah MH, et al. Phase III trial of sunitinib (Su) in imatinib (Im)-resistant/intolerant GIST with novel statistical analysis of long-term survival to account for crossover. Ann Oncol 2008;19(Suppl. 8):266.

Schurr P, Kohrs D, Reichelt U, Kaifi J, Vashist Y, Bachmann K, et al. Repeated surgery improves survival in recurrent gastrointestinal stromal tumors: a retrospective analysis of 144 patients. Dig Surg 2009;26:229–35.

Shankar S, Stay RM, vanSonnenberg E, Dipiro PJ, Janicek MJ, Demetri GD. CT features of gastrointestinal stromal tumors following treatment with STI-571. Radiology 2002;225(Suppl.):583–4.

Shankar S, vanSonnenberg E, Desai J, Dipiro PJ, Van den AA, Demetri GD. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology 2005;235:892–8.

Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M. Mutations in gastrointestinal stromal tumors: a population-based study from Northern Norway. APMIS 2007;115:289–98.

Steinert DM, Blakely LJ, Patel SR, Burgess MA, Chen LL, Trent JC, et al. Outcomes of gastrointestinal stromal tumors (GIST) and other intra-abdominal sarcomas (IAS) in the era of imatinib therapy. J Clin Oncol 2004;22:9047.

Tryggvason G. Clinical study on gastrointestinal stromal tumors (GIST) in Iceland, 1990–2003. Dig Dis Sci 2007;52:2249–53.

Tzen CY. Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors. Eur J Surg Oncol 2008;34:563–8.

Van den Abbeele AD, Badawi RD, Cliche J, Israel DA, Dimitrijevic S, Demetri GD. Response to imatinib mesylate (GleevecTM) therapy in patients with advanced gastrointestinal stromal tumors (GIST) is demonstrated by F-18-FDG-PET prior to anatomic imaging with CT. Radiology 2002;225(Suppl.):424.

Van den Abbeele AD, Badawi RD, Manola J, Morgan JA, Desai J, Kazanovicz A, et al. Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning. J Clin Oncol 2004;22:3012.

Vanel D, Albiter M, Shapeero L, Le Cesne A, Bonvalot S, Le Pechoux C, et al. Role of computed tomography in the follow-up of hepatic and peritoneal metastases of GIST under imatinib mesylate treatment: a prospective study of 54 patients. Eur J Radiol 2005;54:118–23.

Zalinski S, Palavecino M, Abdalla EK. Hepatic resection for gastrointestinal stromal tumor liver metastases. Hematol Oncol Clin N Am 2009;23:115.

Intervention not relevant (n = 15)

Awasthi R, Forrest J, Toy E, Sarsfield P. A review of gastro-intestinal stromal turnours (GISTs) presenting at a single hospital in a twenty year period. J Pathol 2006;208(Suppl. S):54.

Bauer S, Hubert C, Heinrich MC, Cohen P, Bertagnolli M, Demetri GD, et al. KIT hyperactivation in imatinib-resistant GIST: implications for salvage therapies. J Clin Oncol 2005;23:S824.

Bilimoria KY. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 2009;249:63–71.

Chirieac LR, Trent JC, Steinert DM, Choi H, Yang Y, Zhang J, et al. Correlation of immunophenotype with progression-free survival in patients with gastrointestinal stromal tumors treated with imatinib mesylate. Cancer 2006;107:2237–44.

Egberts J-H. Small bowel cancer: single-centre results over a period of 12 years. Hepatogastroenterology 2007;54:129–34.

Gupta M, Sheppard BC, Corless CL, Blanke CD, Billingsley KG. Outcome following aggressive surgical therapy for gastrointestinal stromal tumor. Gastroenterology 2005;128(Suppl. 2):63.

Joensuu H, De Braud F, Coco P, De Pas T, Putzu C, Spreafico C, et al. Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate. Ann Oncol 2008;19:173–7.

Lau S, Lui CY, Yeung YP, Lam HS, Mak KL. Gastrointestinal stromal tumor of rectum: a report of 2 cases. J Comput Assist Tomogr 2003;27:609–15.

Leahy M, Ray-Coquard I, Verweij J, Le Cesne A, Duffaud F, Hogendoorn PC, et al. Brostallicin, an agent with potential activity in metastatic soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2007;43:308–15.

Pauls K, Hohenberger P, Merkelbach-Bruse S, Pietsch T, Heinicke T, Buettner R, et al. Correlation of the c-kit mutational status of gastrointestinal stromal tumors with the clinical response to the tyrosine kinase inhibitor imatinib. Path Res Pract 2004;200:316–17.

Unalp HR, Derici H, Kamer E, Bozdag AD, Tarcan E, Onal MA. Gastrointestinal stromal tumours: outcomes of surgical management and analysis of prognostic variables. Can J Surg 2009;52:31–8.

Wagner AJ, Yazji S, Morgan JA, Choy E, George S, Hohos M, et al. A phase II study of the KIT inhibitor XL820 in patients with advanced gastrointestinal stromal tumors (GIST) resistant to or intolerant of imatinib and/or sunitinib. Eur J Cancer 2008;6(Suppl.):67.

Wise SC, Smith BD, Booth R, Kaufman MD, Lu WP, Petillo PA, et al. Small molecule modulators of KIT kinase for treatment of gastrointestinal stromal tumors (GIST). Inhibitors of juxtamembrane domain, D816V, T670I and V654A mutant forms. Proceedings of the American Association for Cancer Research Annual Meeting 2009, Denver, CO, 18–22 April, p. 50.

Wozniak A, Rutkowski P, Sciot R, De IW, Ruka W, Schoffski P, et al. Analysis of genomic imbalances in imatinib-resistant, progressive gastrointestinal stromal tumors by array comparative genomic hybridization (aCGH). Cell Oncol 2008;30:280–1.

You YQ, Hassan I, Shyyan R, Que FG, Smyrk TC, Donohue JH. Surgical pathology and outcome of gastrointestinal stromal tumors of the stomach. Gastroenterology 2004;126(Suppl. 2):61.

Treatment not evaluated (n = 11)

Bumming P, Ahlman H, Andersson J, Meis-Kindblom JM, Kindblom LG, Nilsson B. Population-based study of the diagnosis and treatment of gastrointestinal stromal tumours. Br J Surg 2006;93:836–43.

Changchien CR, Wu MC, Tasi WS, Tang R, Chiang JM, Chen JS, et al. Evaluation of prognosis for malignant rectal gastrointestinal stromal tumor by clinical parameters and immunohistochemical staining. Dis Colon Rectum 2004;47:1922–9.

Dupart J, Trent JC, Cohen P, Zhang W. Imatinib mesylate activates IGFBP3 expression in gastrointestinal stromal tumors. Clin Cancer Res 2005;11:S8987.

Dupart JJ, Trent JC, Lee HY, Chiao PJ, Godwin AK, Zhang W. IGFBP3 induces apoptosis in gastrointestinal stromal tumors but does not mediate response to imatinib mesylate. Proceedings of the American Association for Cancer Research Annual Meeting 2009, Denver, CO, 18–22 April, p. 50.

Fernandez A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, et al. An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 2007;117:4044–54.

Fletcher JA, Corless CL, Liegl B, Fletcher CD, Raut CP, Donsky R, et al. KIT mutations and sunitinib resistance in gastrointestinal stromal tumors (GISTs). Eur J Cancer 2007;5:S7503.

Koay MHE. Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases. Pathology 2005;37:22–31.

Kurtzman D, Malladevan D. Small molecule therapy: overcoming imatinib resistance in gastrointestinal stromal tumors. J Investig Med 2008;56:80.

Liegl B, Kepten I, Donsky R, Fletcher CDM, Corless CL, Fletcher JA. Morphologic and molecular heterogeneity in imatinib-resistant GIST. Mod Pathol 2008;21(Suppl. 1):51.

Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol 2006;30:477–89.

Yokoi K, Tanaka N, Shoji K, Ishikawa N, Seya T, Horiba K, et al. A study of histopathological assessment criteria for assessing malignancy of gastrointestinal stromal tumor, from a clinical standpoint. J Gastroenterol 2005;40:467–73.

No relevant outcomes (n = 10)

Abecasis MM, Lage P, Salazar M, Freire J, Moreira A, Jorge M, et al. Unlike CML patients, patients with gastrointestinal stromal tumors (GIST) treated with imatinib do not develop hematopoietic clonal cytogenetic abnormalities. Blood 2004;104:4702.

Antonescu CR, Guo T, Arkun K, Dematteo RP, Besmer P. Acquired resistance to imatinib in gastrointestinal stromal tumor (GIST) occurs through secondary gene mutation. Mod Pathol 2005;18(Suppl. 1):33.

Antonescu CR, Guo T, Arkun K, Dematteo RP, Besmer P. Acquired resistance to imatinib in gastrointestinal stromal tumor (GIST) occurs through secondary gene mutation. Lab Invest 2005;85(Suppl. 1):33.

Pricl S, Ferrone M, Fermeglia M, Tamborini E, Delia D, Pierotti MA, et al. C-kit mutants in GISTs and their interaction with STI 571: insights from computer simulations and clinical trials. Abs Pap Am Chem Soc 2003;225(1–2):24.

Raut C, Morgan J, Quigley M, George S, Wagner A, Demetri G, et al. Clinical experience with perioperative sunitinib and extensive resection of imatinib-resistant metastatic GIST. Ann Oncol 2007;18(Suppl. 7):VII123.

Rink L. Correlation of gastrointestinal stromal tumor (GIST) gene expression signatures and response to imatinib mesylate in the RTOG phase II clinical trial S-0132. J Clin Oncol 2009;27(15S):Abstract 10533.

Schoffski P, Huang X, Demetri GD, Casali R, Garrett CR, Blackstein M, et al. Assessment of plasma levels of soluble KIT (sKIT) as a potential surrogate marker for TTP in patients (pts) with advanced gastrointestinal stromal tumor (GIST) treated with sunitinib. Eur J Cancer 2007;5(Suppl.):7502.

Van den Abbeele AD, Melenevsky Y, de Vries D, Manola J, Dileo P, Tetrault R, et al. FDG-PET imaging demonstrates kinase target inhibition by sunitinib malate (SU11248) in GIST patients resistant to or intolerant of imatinib mesylate. Eur J Cancer 2005;3:S202–3.

Van den Abbeele A, Melenevsky Y, de Vries D, Manola J, Dileo P, Tetrault R, et al. Imaging kinase target inhibition with SU11248 by FDG-PET in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (I-R GIST). J Clin Oncol 2005;23:S817.

Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127–34.

Other reasons (n = 61)

Andtbacka RH, Ng CS, Scaife CL, Cormier JN, Hunt KK, Pisters PW, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 2007;14:14–24.

Artinyan A, Kim J, Soriano P, Chow W, Bhatia S, Ellenhorn JD. Metastatic gastrointestinal stromal tumors in the era of imatinib: improved survival and elimination of socioeconomic survival disparities. Cancer Epidemiol Biomark Prevent 2008;17:2194–201.

Bakshi CA, Jain RA, Sastry PS, Sainani AR, Advani SH. Imatinib in gastrointestinal stromal tumors. J Assoc Physicians India 2004;52:403–9.

Basu S, Mohandas KM, Peshwe H, Asopa R, Vyawahare M. FDG-PET and PET/CT in the clinical management of gastrointestinal stromal tumor. Nucl Med Commun 2008;29:1026–39.

Bauer S, Hartmann JT, Lang H, Antoch G, Dirsch O, Ebeling P, et al. Imatinib may enable complete resection in previously unresectable or metastatic GIST. J Clin Oncol 2004;22:9023.

Bauer S, Hartmann JT, de Wit M, Lang H, Grabellus F, Antoch G, et al. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer 2005;117:316–25.

Berman J, O’Leary TJ. Gastrointestinal stromal tumor workshop. Hum Pathol 2001;32:578–82.

Blay JY, Le Cesne A. Gastrointestinal stromal tumors: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol 2007;18:27–9.

Blay J, George S, Casali P, Le Cesne A, Morgan J, Pokela J, et al. Clinical activity and tolerability of continuous daily dosing of sunitinib in patients with advanced GIST. Ann Oncol 2007;18(Suppl. 7):VII24.

Blay J, George S, Casali PG, Le Cesne A, Ray-Coquard I, Harmon CS, et al. Efficacy, safety, pharmacokinetic and pharmacodynamic analysis of sunitinib (Su) adminstered on a continuous daily dosing (CDD) schedule in patients with advanced GIST. Ann Oncol 2008;19(Suppl. 8):267–8.

Blay JY, Berthaud P, Perol D, Ray-Coquard I, Bui B, Duffaud F, et al. Continuous vs intermittent imatinib treatment in advanced GIST after one year: a prospective randomized phase III trial of the French Sarcoma Group. J Clin Oncol 2004;22:9006.

Blay JY, George S, Casali PG, Le Cesne A, Morgan JA, Tyler A, et al. Clinical benefit of continuous daily dosing of sunitinib in patients (pts) with advanced gastrointestinal stromal tumor (GIST). Ann Oncol 2006;17(Suppl. 9):163.

Blay JY, George S, Casali R, Le Cesne A, Morgan JA, Pokela J, et al. Continuous daily dosing (CDD) study of sunitinib malate (SU) in patients (pts) with advanced GIST compares favorably with intermittent dosing. Eur J Cancer 2007;5:S7501.

Boukovinas IP. Advancing treatment of gastrointestinal stromal tumors (GIST). Ann Gastroenterol 2007;20:75–7.

Casali P, Fumagalli E, Bello A, George S. Initiation of sunitinib treatment 24 hours following a final dose of imatinib in patients with advanced gastrointestinal stromal tumor: safety and tolerability. Ann Oncol 2008;19(Suppl. 8):74.

Das S, Mukhopadhyay S, Garai J, Biswas S, Sarkar R, Ghosh P, et al. Tolerance of imatinib mesylate in chronic myeloid leukemia and gastro intestinal stromal tumours patients: an experience from India. Ann Oncol 2006;17(Suppl. 3):51.

Davis DW, McConkey DJ, Heymach JV, Desai J, George S, Deprimo SE, et al. Correlation of receptor tyrosine kinase (RTK) activity and apoptosis with response to sunitinib treatment in patients with gastrointestinal stromal tumor (GIST). Eur J Cancer 2006;4:S57.

Demetri GD, Van Oosterom AT, Blackstein M, Garrett C, Shah M, Heinrich M, et al. Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST. J Clin Oncol 2005;23:S308.

Desai J, Shankar S, Heinrich MC, Fletcher JA, Fletcher CD, Manola J, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 2007;13:5398–405.

Duffaud F, LeCesne A, Ray-Coquard I, Bompass E, Assi K, Berthaud P, et al. Erythropoietin for anemia treatment of patients with GIST receiving imatinib. J Clin Oncol 2004;22:9046.

Eilber FC, Rosen G, Forscher C, Nelson SD, Dorey F, Eilber FR. Recurrent gastrointestinal stromal sarcomas. Surg Oncol 2000;9:71–5.

Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42–7.

Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25–35.

George S, Casali P, Blay J, Le Cesne A, Tyler A, Quigley M, et al. Continuous daily dosing of sunitinib in patients with advanced GIST: initial results of a phase II study. Ann Oncol 2006;17(Suppl. 6):28.

George S, Casali PG, Blay J, Le Cesne A, Tyler AR, Quigley MT, et al. Phase II study of sunitinib administered in a continuous daily dosing regimen in patients (pts) with advanced GIST. J Clin Oncol 2006;24:9532.

George S, Blay J, Casali P, Le Cesne A, Morgan J, Pokela J, et al. Continuous daily dosing (CDD) of sunitinib malate (SU) compares favorably with intermittent dosing in pts with advanced GIST. J Clin Oncol 2007;25(Suppl. 18):Abstract 10015.

George S, Blay JY, Casali P, Le Cesne A, Deprimo S, Harmon CS, et al. Continuous daily dosing of sunitinib in patients with advanced GIST: updated efficacy safety PK and pharmacodynamic analysis. J Clin Oncol 2008;26(Suppl. 5): Abstract 10554.

George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 2009;45:1959–68.

Gold JS. Outcome of metastatic GIST in the era before tyrosine kinase inhibitors. Ann Surg Oncol 2007;14:134–42.

Gold JS, van der Zwan SM, Gonen M, Maki RG, Singer S, Brennan MF, et al. Outcome of metastatic GIST in the era before imatinib mesylate. Ann Surg Oncol 2006;13:29.

Gronchi A, Fiore M, Bertulli R, Colecchia M, Tamborini E, Pilotti S, et al. Surgery of residual disease following imatinib mesylate in advanced gastrointestinal stromal tumors (GIST). J Clin Oncol 2005;23:825S.

Holdsworth CH, Badawi RD, Manola JB, Kijewski MF, Israel DA, Demetri GD, et al. CT and PET: early prognostic indicators of response to imatinib mesylate in patients with gastrointestinal stromal tumor. Am J Roentgenol 2007;189:W324–30.

Houk BE, Bello C, Garrett M, Poland B, Wagg J, Wada R, et al. Population pharmacokinetic (PK)-pharmacodynamic (PD) meta-analysis of sunitinib malate (SU11248) efficacy and tolerability endpoints in gastrointestinal stromal tumor (GIST), metastatic renal cell carcinoma (MRCC) and solid tumor patients. Clin Cancer Res 2005;11:S9075-6.

Houk B, Bello C, Cohen D, Casali P, Shirao K, Demetri G. An exposure-response-based meta-analysis of the efficacy of sunitinib in patients with gastrointestinal stromal tumor. Ann Oncol 2008;19(Suppl. 8):11–12.

Houk BE, Bello C, Cohen D, Kuwabara-Wagg J, Poland B. A sunitinib exposure-effect based meta-analysis of treatment-related adverse events (TRAEs) in patients with metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Clin Pharmacol Ther 2008;83(Suppl. 1):53.

Houk BE, Bello CL, Demetri GD, Michaelson M, Casali PG, Bukowski RM, et al. Comparative efficacy of sunitinib administered on an intermittent or a continuous daily dosing schedule in metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) patients predicted using population PK approaches. Proceedings of the American Association for Cancer Research Annual Meeting, San Diego, CA, 12–16 April 2008: 49.

Houk B, Kang D, Bello C, Cohen D, Poland B. Impact of demographic and clinical factors on the pharmacokinetics (PK) of sunitinib in patients and healthy volunteers. Clin Pharmacol Ther 2008;83(Suppl. 1):53–4.

Houk BE, Bello CL, Kang D, Amantea M. A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res 2009;15:2497–506.

Hsieh CB, Shih ML, Yu JC, Lee HS, Chen DW, Chao TY, et al. Giant malignant gastrointestinal stromal tumors (> 10cm): recurrent factors and effect of STI 571 treatment. XXXIII World Congress of the International College of Surgeons 2002;119–23.

Huang CC, Yang CY, Lai IR, Chen CN, Lee PH, Lin MT. Gastrointestinal stromal tumor of the small intestine: a clinicopathologic study of 70 cases in the postimatinib era. World J Surg 2009;33:828–34.

Judson I. Imatinib in the treatment of gastrointestinal stromal tumour. Anal Cell Pathol 2003;25:23.

Kang Y, Kang BW, Ryu M, Im S, Park SR, Kang WK, et al. A phase II study of imatinib mesylate as adjuvant treatment for curatively resected high-risk localized gastrointestinal stromal tumors with C-Kit exon 11 mutation. Ann Oncol 2008;19(Suppl. 8):169.

Keun PC, Lee EJ, Kim M, Lim HY, Choi DI, Noh JH, et al. Prognostic stratification of high-risk gastrointestinal stromal tumors in the era of targeted therapy. Ann Surg 2008;247:1011–18.

Mabille M, Vanel D, Albiter M, Le Cesne A, Bonvalot S, Le Pechoux C, et al. Follow-up of hepatic and peritoneal metastases of gastrointestinal tumors (GIST) under imatinib therapy requires different criteria of radiological evaluation (size is not everything!!!). Eur J Radiol 2009;69:204–8.

McAuliffe JC, Lazar AJ, Yang D, Steinert DM, Qiao W, Thall PF, et al. Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate. Clin Cancer Res 2007;13:6727–34.

Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors (GISTs) of the jejunum and ileum: a clinicopathologic, immunohistochemical and molecular genetic study of 906 cases prior to imatinib with long-term follow-up. Lab Invest 2006;86:56.

Miettinen M, Makhlouf H, Sobin L, Lasota J. Gastrointestinal stromal tumors (GISTs) of the jejunum and ileum: a clinicopathologic, immunohistochemical and molecular genetic study of 906 cases prior to imatinib with long-term follow-up. Mod Pathol 2006;19(Suppl. 1):15A.

Mindikoglu AL, Regev A, Bejarano PA, Martinez EJ, Jeffers LJ, Schiff ER. Imatinib mesylate (Gleevec) hepatotoxicity. Dig Dis Sci 2007;52:598–601.

Mukhopadhyay A, Barman B, Sen A, Sarkar S, Gupta P, Deb A, et al. Tolerance of imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumours patients: an experience from India. Ann Oncol 2005;16(Suppl. 2):304.

Paul C, Mukhoapdhyay S, Mondal AK, Chitalkar PG, Mukhoapdhyay A. Imatinib mesylate as first line therapy in patients with gastrointestinal stromal tumour (GIST). An experience from India. Ann Oncol 2007;18(Suppl. 4):40.

Perik PJ, Rikhof B, de Jong FA, Verweij J, Gietema JA, Van der Graaf WT. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity. Ann Oncol 2008;19:359–61.

Raut C, Morgan JA, Quigley MT, George S, Wagner AJ, Demetri G, et al. Postoperative experience in patients with metastatic GIST are similar in patients while on sunitinib or imatinib. Eur J Cancer 2007;5:S7522.

Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006;24:2325–31.

Reichardt P, Pink D, Lindner T, Heinrich MC, Cohen PS, Wang Y, et al. A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. J Clin Oncol 2005;23:S196.

Rock EP, Goodman V, Jiang JX, Mahjoob K, Verbois SL, Morse D, et al. Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007;12:107–13.

Shen L, Li J, Li J, Gong J, Wu A. Adjuvant post-surgery therapy with imatinib in intermediate or high-risk gastrointestinal stromal tumour (GIST) patients: interim analysis from a single centre comparison study. Ann Oncol 2008;19(Suppl. 8):267.

Siehl J, Thiel E. C-kit, GIST, and imatinib. Recent Results Cancer Res 2007;176:145–51.

Trent JC, Choi H, Hunt K, Macapinlac H, McConkey D, Charnsangravej C, et al. Apoptotic and anti-vascular activity of imatinib in GIST patients. J Clin Oncol 2005;23:S816.

Ullrich A. Targeted cancer therapies: herceptin and SUTENT. FEBS J 2008;275(Suppl. 1):11.

Usman M. Hematological and nonhematological toxicities of imatinib mesylate in patients with chronic myeloid leukemia and gastrointestinal stromal tumor. Ind J Pharmacol 2007;39:192–5.

Wu PC, Langerman A, Ryan CW, Hart J, Swiger S, Posner MC. Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era. Surgery 2003;134:656–65.

Not obtained/received too late (n = 47)

ASCO 2007 updates. Sunitinib in the treatment of metastatic renal carcinoma and the gastrointestinal stromal tumors. Tumori 2007;93(Suppl. 5):1–16.

Don’t interrupt imatinib in GIST patients. Oncol News Int 2007;16:1.

Focus on hematology, Gleevec postsurgery sharply reduces GIST recurrences. Oncol News Int 2007;16:42.

Focus on hematology. Long-term imatinib recommended for metastatic GIST even after complete resection, French study shows. Oncol News Int 2006;15:30.

Imatinib for the treatment of life-threatening gastrointestinal cancer. Dtsch Apoth Ztg 2002;142:40–2.

Aliberti S, Grignani G, Bordonaro R. TK-inhibitors in the clinical management of GIST. What’s up, what’s next? Supp Palliat Cancer Care 2006;2:143–6.

Anton CR, Balan G. [Gastrointestinal stromal tumors. Actual diagnosis and treatment.] Rev Med Chir Soc MedNatIasi 2005;109:223–9.

Baldo S, Rivoire M, Sobrero A, Comandini D, Civalleri D, Stella M, et al. [Surgical resection of gastrointestinal stromal tumor after treatment with imatinib: clinical case.] Suppl Tumori 2005;4:S97.

Beheshti M. The potential value of F-18 FDG PET in comparison to CT in early prediction of response to imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. Iran J Nucl Med 2007;15:34–42.

Beijnen JH. Recent developments in pharmacotherapy of cancer. Pharm Weekbl 2007;142:2–7.

Belev B, Vrbanec D, Kralik M, Plestina S, Petricevic B, Sirotkovic-Skerlev M. Gastrointestinal stromal tumors (GIST): a paradigm of successful targeted therapy of solid tumors. Acta Med Croatica 2006;60:471–5.

Buchner-Steudel P, Fleig WE. [Diagnosis and conservative treatment of gastrointestinal stromal tumors (GIST).] Deutsche Medizinische Wochenschrift 2004;129:1808–10.

Cabebe E, Wakelee H. Sunitinib: a newly approved small-molecule inhibitor of angiogenesis. Drugs Today 2006;42:387–98.

Casali PG. Selective tyrosine kinase inhibitors: imatinib in GIST. Tumori 2003;89:S42–3.

Delmonte L. Good results continue for Gleevec for GIST… Metastatic gastrointestinal stromal tumors. Oncology Times 2002;13–14.

Eisenberg B. GIST adjuvant therapy – some answers and more questions. Nature Rev Clin Oncol 2009;6:441–2.

Fath R. Effectiveness of imatinib in GIST continues for the long-term. Z Gastroenterol 2006;44:9.

Feldman B. Getting the gist of GIST… gastrointestinal stromal tumor. J GENCA 2007;17:13–17.

Fuerst ML. GIST: molecular tests predict response to imatinib. Oncology Times 2005;18.

Gale S. 27th Annual JPMorgan Healthcare Conference – Biogen Idec. IDrugs 2009;12:140–1.

Gluszek S, Rylski R, Kot M, Stanislavek J, Karoz W, Urbaniak A, et al. GIST: risk of recurrence and dissemination. PRZ Gastroenterol 2008;3:176–84.

Gordon JK, Magid SK, Berman E. Elevations in creatine kinase occur frequently in patients treated with imatinib mesylate (Gleevec). Arthritis Rheum 2008;58:25.

Helwick C. Focus on hematology. Good survival with adjuvant imatinib for high-risk GIST. Oncol News Int 2008;17:28.

Houk BE, Bello C, Cohen DP, Demetri GD, Casali PG, Shirao K. Efficacy of sunitinib in patients with gastrointestinal stromal tumor (GIST): an exposure-response based meta-analysis. Mol Cancer Ther 2007;6:S3589.

Jimeno J. Gastrointestinal stromal tumors: surgical treatment. Gastroenterologia y Hepatologia Continuada 2009;8:82–6.

Joensuu H. Treatment of inoperable gastrointestinal stromal tumor (GIST) with imatinib (Glivec, Gleevec). Med Klin 2002;97(Suppl.):128–30.

Jost D, Stroszczynski C, Chmelik P, Gaffke G, Schlecht I, Pink D, et al. [Morphology of gastrointestinal stromal tumors in advanced stages of the disease: baseline findings before chemotherapy with imatinib]. Rofo 2003;175:791–8.

Kale SS. A case and literature review of complicated gastrointestinal stromal tumors. Gastroenterol and Hepatol 2008;4:650–7.

Khadija B. Gastrointestinal stromal tumor: epidemiology and outcome study in 40 cases. Tunis Med 2006;84:26–9.

Kitamuru Y, Hirota S, Nishida T. Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. Gann Monograph on Cancer Research no. 53: gastrointestinal stromal tumor (GIST): from pathology to molecular target therapy. Karger; 2004. pp. 27–40.

Le Cesne A. C-KIT and GIST: rational use of Glivec in gastrointestinal stromal tumors. Ann Pathol 2002;22:S1–4.

McIntyre JA. Sunitinib malate: oncolytic drug multitargeted tyrosine kinase inhibitor. Drugs Future 2005;30:785–92.

Mansueto G, Longo F. [News on ASCO 2007. Sunitinib in the treatment of metastatic renal carcinoma and gastrointestinal stromal tumors.] Tumori 2007;93(Suppl.):16.

Masche UP. Sunitinib. Pharma-Kritik 2006;28:39.

Mosnier J-F. Gastrointestinal stromal tumors: from gene to treatment. Hepatogastroenterology 2002;9:403–6.

Motzer RJ. Sunitinib. Drugs 2006;66:2267.

Prenen H, Dumez H, Stefan C, Hoeben A, Wouters C, Van Lierde MA, et al. Imatinib for the treatment of patients with unresectable or metastatic malignant KIT-positive gastrointestinal stromal tumours: an open-label Belgian trial. Acta Gastroenterol Belg 2006;69:367–71.

Raccah E, Merimsky O, Kuten A, Apter S, Catane R. [Imatinib mesylate (glivec) as a treatment for gastrointestinal stromal tumor (GIST): long term follow-up.] Harefuah 2007;146:329–34.

Raut CP, Hornick JL, Bertagnolli MM. Gastrointestinal stromal tumors of gastric origin. In Wang TC, Fox JG, Giraud AS, editors. The biology of gastric cancers. New York, NY: Springer; 2009. pp. 135–63.

Raut CP. Advanced gastrointestinal stromal tumor: potential benefits of aggressive surgery combined with targeted tyrosine kinase inhibitor therapy. Am J Oncol Rev 2006;5:707–12.

Rutkowski P. Gastrointestinal stromal tumors: clinical and morphological features. Pol Przegl Chir 2003;75:374–84.

Sanchez MRG. Gastrointestinal stromal tumors: medical treatment. Gastroenterologia y Hepatologia Continuada 2009;8:87–90.

Schutte J. Gastrointestinal stromal tumors (GIST): systemic treatment with imatinib and treatment monitoring. Tumor Diagnostik und Therapie 2004;25:174–6.

Sebastian M. Aggressive surgery combined with targeted tyrosine kinase inhibitor therapy in advanced gastrointestinal stromal tumor: a commentary. Am J Oncol Rev 2006;5:715–16.

Szawlowski AW. Observation results of patients with gastrointestinal stromal tumors (GIST) subjected to surgical treatment: commentary. Pol Przegl Chir 2006;78:581–2.

Van den Abbeele AD. FDG-PET to measure response to targeted therapy: the example of gastrointestinal stromal tumor and imatinib mesylate (Gleevec). PET Clinics 2008;3:77–87.

Yokoyama A, Dairaku N, Kusano M, Koshita S, Shimada N, Yamagiwa T, et al. [Two cases of primary unresectable and/or recurrent gastrointestinal stromal tumors of small intestine presenting hemoperitoneum caused by administration of imatinib mesylate.] Nippon Shokakibyo Gakkai Zasshi – Japn J Gastroenterol 2008;105:1619–26.

Blanke B2222 study

Blanke S0033 study

EORTC-ISG-AGITG (62005) study

Park 2009

Seddon 2008

Title of the project

• Imatinib at escalated doses of 600 mg/day or 800 mg/day for the treatment of people with unresectable and/or metastatic GISTs whose disease has progressed on treatment with imatinib at a dose of 400 mg/day: systematic review and economic evaluation

Name of technology assessment review (TAR) team and ‘lead’

Aberdeen HTA Group

Jenni Hislop

Research Fellow, Systematic Reviewer

Health Services Research Unit (HSRU)

3rd Floor

University of Aberdeen

Health Sciences Building

Foresterhill

Aberdeen

AB25 2ZD

Plain English summary

Gastrointestinal stromal tumours (GISTs) are a rare type of cancerous tumours that most commonly arise in the stomach or small intestine. People will be diagnosed with this type of cancer only if a biopsy of their tumours tests positive for a particular protein (called ‘KIT’ or ‘CD117’). In around half of all cases it is possible to remove the tumour surgically; however, overall at least 50% of those operated on will develop recurrent disease within 5 years. In these patients with recurrence, and other patients with inoperable disease at diagnosis, survival beyond a period of 2 years is uncommon without further treatment. The usual treatment for patients with inoperable GISTs is the drug imatinib, prescribed at a dose of 400 mg per day. Over 75% of patients will show either response or stable disease (SD) with the standard dose of imatinib, which typically provides control of the GISTs for a period of 2–3 years. Approximately 50% of patients will survive 5 years or more with this treatment. However, in all patients, resistance of the GISTs to imatinib will eventually occur and the disease will then progress. Genetic differences, for example whether certain mutations in the c-KIT or CD117 gene are present in patients or not, may help clinicians’ understanding of who is more likely to be able to tolerate the drug and/or have least resistance to it. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans may also be useful to detect early response or resistance to imatinib and these measures may allow more individualised treatment approaches. At present, increasing the dose of imatinib, when 400 mg per day ceases to improve a patient’s condition, is not officially recommended (although in practice it is usually tried). An alternative drug (sunitinib) is recommended to be prescribed in cases where imatinib has failed. The only other alternative to these treatments for patients with inoperable GISTs is to provide BSC through management of the patient’s pain and other symptoms, and attend to their needs and general well-being, without providing treatment to actively fight the cancer itself. However, in reality it is likely that all patients (including those receiving active treatment) will receive supportive care as part of this treatment.

This review will look at two alternative doses of imatinib (600 and 800 mg per day) and compare these with the current recommended treatment alternatives (i.e. sunitinib and/or BSC) for those patients with inoperable GISTs whose disease progresses while on imatinib at a dose of 400 mg per day.

Decision problem

Gastrointestinal stromal tumours are tumours of the connective tissue of the gastrointestinal (GI) tract arising in the interstitial cells of Cajal. They are rare cancers and estimated to account for 1% of all tumours arising in the GI tract. 1 It is estimated that the vast majority (between 60% and 70%) will arise in the stomach, though they can also occur in the small bowel (25–35%), colon and rectum (5%), and, to a lesser extent, the oesophagus. 2 Estimates of the number of people affected by GIST vary, but it is thought that the annual incidence is unlikely to exceed 240. 3 However, previous estimates have suggested that it could be as high as 2000 cases per year. 3 The median age at time of first presentation is approximately 60 years. 4 Prognosis for patients with GISTs is highly dependent on the resectability of the tumour and approximately half of patients with GISTs will have resectable disease at first presentation. GISTs are resistant to the ‘conventional’ oncology treatments of cytotoxic chemotherapy and radiotherapy. For resectable/non-metastatic tumours, prognosis gives a 10-year survival rate of 30–50% of patients, and at least 50% will relapse within 5 years,5 but for unresectable tumours prognosis is poor, with survival generally < 2 years without further treatment. 6

For a GIST to be diagnosed, it is widely accepted that a positive test result (at protein level) for the marker KIT (CD117) is required. KIT (CD117) is a tyrosine kinase receptor that provides a major pathogenic drive for the majority of GISTs by promoting tumour growth and inhibiting tumour cell death. There has been some debate on the definition of a GIST, as it has been noted that in extremely rare cases (< 5%) a patient can have a GIST despite testing negative for c-KIT protein expression and in most of these cases a mutation of the platelet-derived growth factor receptor alpha (PDGFRA) gene has been detected. 7–9 However, the World Health Organization (WHO) classification of GI tumours recommends that a diagnosis of GIST should only apply to those patients testing positive for the KIT (CD117) protein. 10

Imatinib is manufactured by Novartis under the names Glivec^® (in Europe) and Gleevec^® (in the USA). Having originally been licensed as a treatment for chronic myeloid leukaemia, it was first licensed for treatment of GIST in 2002 and is now the standard first-line treatment for ‘locally advanced, inoperable patients and metastatic patients’ with GIST. 11 The 2004 National Institute for Health and Clinical Excellence (NICE) Technology Appraisal no. 86 on the use of imatinib for the treatment of unresectable and/or metastatic GISTs recommends 400 mg per day as first-line management. At present the NICE guidance does not recommend dose escalation of imatinib for those whose disease progresses after initially responding at the 400 mg per day dose, although dose escalation has been noted to be the standard approach to disease progression where patient non-adherence or intolerance to imatinib are not factors in disease progression. 11

The alternative treatments available for unresectable and/or metastatic GISTs are sunitinib (manufactured by Pfizer) and best supportive care (BSC). Sunitinib is recommended for patients with unresectable and/or metastatic GISTs if treatment with imatinib has failed because of resistance or intolerance, and the drug cost for the first treatment cycle will be met by the manufacturer. 12 BSC is less well defined or standardised in different clinical trials or treatment protocols, and has also been referred to as ‘active symptom control’. 2 It has been said to involve interventions to manage pain, treat fever, anaemia (due to GI haemorrhage) and GI obstruction,1 and can include palliative measures. 13 In a Cochrane review of supportive care for patients with GI cancer, supportive care was defined as ‘the multi-professional attention to the individual’s overall physical, psychosocial, spiritual and cultural needs’. 14 It was argued that this type of care should ethically be made available to all treatment groups, meaning that in practice for patients with GISTs, treatment with imatinib or sunitinib would not be provided without supportive care as well, though it is possible that treatment with BSC could be provided without additional drug treatment with either imatinib or sunitinib.

The survival of patients with GISTs is largely dependent on whether or not the tumour is resectable. For patients with unresectable and/or metastatic disease, the treatment options are imatinib, sunitinib or BSC. Guidance is available on the effectiveness of imatinib at the 400 mg per day dose. 1 However, assessment is required of the clinical effectiveness of imatinib at higher dosages (i.e. 600 and 800 mg per day) in patients whose disease has progressed on treatment with the 400 mg dose, given that an estimated 16% of patients will experience primary resistance to imatinib, and all will develop resistance and progressive disease (PD) at a later stage. 15 In evaluating the effectiveness of escalated doses of imatinib or other alternate treatments it is also necessary to consider subgroups of patients with specific KIT mutations who may respond differently to treatment, and also note how rapidly, and by what method (e.g. FDG-PET scans), these patients were identified.

This review will assess the clinical effectiveness and cost-effectiveness of imatinib at escalated doses of 600 mg per day, and 800 mg per day, compared with treatment using sunitinib, or BSC, in patients with KIT (CD117)-positive unresectable and/or metastatic malignant GISTs, whose disease has progressed on treatment with imatinib at a dose of 400 mg per day.

Report methods for synthesis of evidence of clinical effectiveness

A systematic review of the evidence of the clinical effectiveness of imatinib at escalated doses of 600 or 800 mg per day will be undertaken following the gen eral principles of the guidance of the Centre for Reviews and Dissemination (CRD) for undertaking reviews in health care16 and reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. 17

Report methods for synthesising evidence of cost-effectiveness

Handling the company submission(s)

Information from the manufacturer will be considered if submitted in accordance with the 3 December 2009 deadline set by NICE. Following receipt of the submission, members of the Aberdeen TAR team will critically appraise sections of the report according to each member’s own area of expertise. Studies reported in the manufacturer’s submission that meet the inclusion criteria for the review will be data extracted and quality assessed in accordance with the procedures outlined in this protocol, and included in the data analysis.

Any economic evaluations included in the company submission, provided they comply with NICE’s guidance on presentation, will be assessed for clinical validity, reasonableness of assumptions and appropriateness of the data used in the economic model, again using the methods outlined in this protocol. Strengths and weaknesses in terms of methodology adopted, reporting of results and conclusions will be described. The default position of the TAR team is that further modelling work will be necessary and if the TAR team judge that the existing economic evidence is not robust then further work will be undertaken, either by adapting what already exists or developing de novo modelling (as described in Economic modelling, above). The conclusions derived from the company submission may then be compared with those provided by the review of the other existing evidence and any model we develop so that differences in results can be highlighted. If the model we may develop differs substantively from that submitted by any company, we shall justify any assumptions made.

Any ‘CiC’ data taken from a company submission will be reported in accordance with NICE guidelines.

Competing interests of authors

None.

Reference list

MEDLINE (2000 – October, week 4 2009), EMBASE (2000–9, week 44), MEDLINE In-Process (3 November 2009)

Science Citation Index (2000, 3 November 2009)

Health Management Information Consortium (September 2009)

NHS Economic Evaluation Database (October 2009), HTA Database (October 2009)

IDEAS (October 2009)

Websites consulted (accessed October 2009)